Vagal nerve stimulation to avert or treat stroke or transient ischemic attack

ABSTRACT

Devices, systems and methods are disclosed for treating or preventing a stroke and/or a transient ischemic attack in a patient. The methods comprise transmitting impulses of energy non-invasively to selected nerve fibers, particularly those in a vagus nerve. Vagus nerve stimulation is used to modulate the release of GABA, norepinephrine, and/or serotonin, thereby providing neuroprotection to the patient; to modulate the activity of resting state neuronal networks, particularly the sensory-motor network or resting state networks containing the insula; and to avert a stroke or transient ischemic attack that has been forecasted.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation in Part of U.S. patent applicationSer. No. 13/603,781 filed Sep. 5, 2012; which is a Continuation in Partof U.S. patent application Ser. No. 13/222,087 filed Aug. 31, 2011;which is a Continuation in Part of U.S. patent application Ser. No.13/183,765 filed Jul. 15, 2011; which is a Continuation in Part of U.S.patent application Ser. No. 13/183,721 filed Jul. 15, 2011; which claimsthe benefit of priority to U.S. Provisional Application No. 61/488,208filed May 20, 2011 and U.S. Provisional Application No. 61/487,439 filedMay 18, 2011.

This application also is a Continuation in Part of U.S. patentapplication Ser. No. 13/109,250 filed May 17, 2011; which claims thebenefit of priority to U.S. Provisional Application No. 61/471,405 filedApr. 4, 2011.

This application also is a Continuation in Part of U.S. patentapplication Ser. No. 13/075,746 filed Mar. 30, 2011; which claims thebenefit of priority to U.S. Provisional Application No. 61/451,259 filedMar. 10, 2011.

This application also is a Continuation in Part of U.S. patentapplication Ser. No. 13/005,005 filed Jan. 12, 2011; which is aContinuation in Part of U.S. patent application Ser. No. 12/964,050filed Dec. 9, 2010; which claims the benefit of priority to U.S.Provisional Application No. 61/415,469 filed Nov. 19, 2010.

This application also is a Continuation in Part of U.S. patentapplication Ser. No. 12/859,568 filed Aug. 19, 2010; which is (1) aContinuation in Part of U.S. patent application Ser. No. 12/612,177filed Nov. 4, 2009, now U.S. Pat. No. 8,041,428 issued Oct. 18, 2011;which is a Continuation in Part of U.S. patent application Ser. No.11/592,095 filed Nov. 2, 2006, now U.S. Pat. No. 7,725,188 issued May25, 2010; which claims the benefit of priority to U.S. ProvisionalApplication No. 60/814,312 filed Jun. 16, 2006 and U.S. ProvisionalApplication No. 60/772,361 filed Feb. 10, 2006; and (2) a Continuationin Part of U.S. patent application Ser. No. 12/408,131 filed Mar. 20,2009; which is a Continuation in Part of U.S. Patent Application No.11/591,340 filed Nov. 1, 2006, now U.S. Pat. No. 7,747,324 issued Jun.29, 2010; which claims the benefit of priority to U.S. ProvisionalApplication No. 60/814,313 filed Jun. 16, 2006, U.S. ProvisionalApplication No. 60/786,564 filed Mar. 28, 2006, U.S. ProvisionalApplication No. 60/772,361 filed Feb. 10, 2006, U.S. ProvisionalApplication No. 60/736,002 filed Nov. 10, 2005, and U.S. ProvisionalApplication No. 60/736,001 filed Nov. 10, 2005.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Theinvention relates more specifically to devices and methods for treatingconditions associated with stroke and/or transient ischemic attacks. Theenergy impulses (and/or fields) that are used to treat those conditionscomprise electrical and/or electromagnetic energy, deliverednon-invasively to the patient.

The use of electrical stimulation for treatment of medical conditions iswell known. For example, electrical stimulation of the brain withimplanted electrodes (deep brain stimulation) has been approved for usein the treatment of various conditions, including pain and movementdisorders such as essential tremor and Parkinson's disease [Joel S.PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu. Rev.Neurosci 29 (2006):229-257].

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92 (2001):505-513; U.S. Pat. No. 6,871,099,entitled Fully implantable microstimulator for spinal cord stimulationas a therapy for chronic pain, to WHITEHURST, et al].

Many other forms of nerve stimulation exist [HATZIS A, Stranjalis G,Megapanos C, Sdrolias P G, Panourias I G, Sakas D E. The current rangeof neuromodulatory devices and related technologies. Acta NeurochirSuppl 97(Pt 1, 2007):21-29]. The type of electrical stimulation that ismost relevant to the present invention is vagus nerve stimulation (VNS,also known as vagal nerve stimulation). It was developed initially forthe treatment of partial onset epilepsy and was subsequently developedfor the treatment of depression and other disorders. The left vagusnerve is ordinarily stimulated at a location within the neck by firstimplanting an electrode about the vagus nerve during open neck surgeryand by then connecting the electrode to an electrical stimulator circuit(a pulse generator). The pulse generator is ordinarily implantedsubcutaneously within a pocket that is created at some distance from theelectrode, which is usually in the left infraclavicular region of thechest. A lead is then tunneled subcutaneously to connect the electrodeassembly and pulse generator. The patient's stimulation protocol is thenprogrammed using a device (a programmer) that communicates with thepulse generator, with the objective of selecting electrical stimulationparameters that best treat the patient's condition (pulse frequency,stimulation amplitude, pulse width, etc.) [Patent numbers U.S. Pat. No.4,702,254 entitled Neurocybernetic prosthesis, to ZABARA; U.S. Pat. No.6,341,236 entitled Vagal nerve stimulation techniques for treatment ofepileptic seizures, to OSORIO et al; U.S. Pat. No. 5,299,569 entitledTreatment of neuropsychiatric disorders by nerve stimulation, toWERNICKE et al; G. C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas.Deep brain stimulation, vagal nerve stimulation and transcranialstimulation: An overview of stimulation parameters and neurotransmitterrelease. Neuroscience and Biobehavioral Reviews 33 (2009):1042-1060;GROVES D A, Brown V J. Vagal nerve stimulation: a review of itsapplications and potential mechanisms that mediate its clinical effects.Neurosci Biobehav Rev 29 (2005):493-500; Reese TERRY, Jr. Vagus nervestimulation: a proven therapy for treatment of epilepsy strives toimprove efficacy and expand applications. Conf Proc IEEE Eng Med BiolSoc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nerve stimulation:current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4; ANDREWS, R.J. Neuromodulation. I. Techniques-deep brain stimulation, vagus nervestimulation, and transcranial magnetic stimulation. Ann. N.Y. Acad. Sci.993 (2003):1-13; LABINER, D. M., Ahern, G. L. Vagus nerve stimulationtherapy in depression and epilepsy: therapeutic parameter settings.Acta. Neurol. Scand. 115 (2007):23-33; AMAR, A. P., Levy, M. L., Liu, C.Y., Apuzzo, M. L. J. Vagus nerve stimulation. Proceedings of the IEEE96(7, 2008):1142-1151; CLANCY J A, Deuchars S A, Deuchars J. The wondersof the Wanderer. Exp Physiol 98(1, 2013):38-45].

In the present invention, electrical and/or magnetic stimulation of avagus nerve is used to avert, treat or manage stroke and/or transientischemic attacks. A stroke is the acute loss of brain function due toloss of normal blood supply to the brain or brainstem, spinal cord, orretina. This can be due to the lack of blood flow (ischemia) caused byblockage of a blood vessel due to thrombosis or arterial embolism.Stroke may also be due to a hemorrhage. A thrombotic stroke occurs whena blood clot (thrombus) forms in one of the brain's arteries, which maybe formed in the vicinity of fatty deposits (plaque) that build up inthe artery to cause reduced blood flow (atherosclerosis). Less commonly,the thrombus may form at the site of a vasospasm of a migraine sufferer.A thrombus can block a large brain artery (causing widespread braindamage) or a small artery, the latter resulting in a so-called lacunarstroke. An embolic stroke occurs when a blood clot or other debris(embolus) forms outside brain, for example in an atrium of the patient'sheart, and is transported through the bloodstream to lodge in an arteryof the brain. About half to two-thirds of all strokes are thromboticstrokes.

Ischemic stroke occurs in 87% of stroke patients and may be eithersymptomatic or silent. Symptomatic ischemic strokes are manifest byclinical signs of focal or global cerebral, spinal, or retinaldysfunction caused by death of neural tissue (central nervous systeminfarction). A silent stroke is a documented central nervous systeminfarction (tissue death due to lack of oxygen) that was asymptomatic.Symptomatic ischemic strokes are usually treated with thrombolyticagents (“clot busters”), preferably within three hours of the onset ofthe stroke. In contrast, hemorrhagic strokes occur in 13% of strokepatients, who may be treated by neurosurgery. Hemorrhagic strokesinclude bleeding within the brain (intracerebral hemorrhage) andbleeding between the inner and outer layers of the tissue covering thebrain (subarachnoid hemorrhage).

A transient ischemic attack (TIA) is also caused by ischemia in thebrain, spinal cord or retina. TIAs share the same underlying etiology asischemic strokes and produce the same symptoms, such as contralateralparalysis, sudden weakness or numbness, dimming or loss of vision,aphasia, slurred speech and mental confusion. Unlike a stroke, thesymptoms of a TIA can resolve typically within a day, whereas thesymptoms from a stroke can persist due to death of neural tissue (acuteinfarction). Thus, a transient ischemic attack may be defined as atransient episode of neurological dysfunction caused by focal brain,spinal cord, or retinal ischemia, without acute infarction [EASTON JD,Saver J L, Albers G W, et al. Definition and evaluation of transientischemic attack: a scientific statement for healthcare professionalsfrom the American Heart Association/American Stroke Association StrokeCouncil et al. Stroke 40(6, 2009):2276-2293; PRABHAKARAN S. Reversiblebrain ischemia: lessons from transient ischemic attack. Curr Opin Neurol20(1, 2007):65-70].

Stroke accounts for approximately 9.7% of all deaths worldwide. It isthe third-leading cause of death in the United States, with more than140,000 people dying of stroke each year. Some 795,000 individualssuffer a stroke annually in the U.S. (269 per 100,000 population), with600,000 of these strokes representing first-time attacks. Stroke alsocauses a substantial medical burden for those individuals who survive astroke. Overall case-fatality within 1 month of stroke onset is about23%, but is higher for intracerebral hemorrhage (42%) and subarachnoidhemorrhage (32%) than for ischemic stroke (16%). Among all nonpediatricpopulations, stroke is the fourth-leading cause of lostdisability-adjusted life-years, behind only to HIV/AIDS, unipolardepressive disorders, and ischemic heart disease. The total cost ofstroke to the United States is estimated at $43 billion per year,consisting of direct costs of medical care and therapy at $28 billionper year and indirect costs from lost productivity and other factors at$15 million per year [Debraj MUKHERJEE and Chirag G. Patil. Epidemiologyand the Global Burden of Stroke. World Neurosurg 76(6 Suppl,2011):S85-S90; FEIGIN V L, Lawes C M, Bennett D A, Anderson C S. Strokeepidemiology: a review of population-based studies of incidence,prevalence, and case-fatality in the late 20th century. Lancet Neurol2(1, 2003):43-53].

The estimated annual number of TIAs in the U.S. is about 200 to 500thousand, although the number is difficult to estimate because TIAs maybe under-reported, considering that they typically last less than anhour. It is not well known by the general public that a TIA is a medicalemergency requiring prompt medical attention. Approximately 10% ofstrokes are preceded by one or more TIAs. An estimated one-third of allTIAs are followed by a stroke within five years [JOHNSTON SC. Transientischemic attack. N Engl J Med. 347 (2002):1687-1692].

The goal of diagnosis of a TIA is to identify the cause of the TIA andto recommend treatment accordingly. With a carotid artery TIA, symptomsand signs are related to the ipsilateral cerebral hemisphere and/orretina. In amaurosis fugax, cholesterol from ruptured atheroscleroticplaques in the common or internal carotid artery or other types ofemboli transiently occludes flow to the retinal artery, causing a suddenonset of monocular blindness. In a certebrobasilar artery TIA, symptomsand signs are related to the posterior cerebral circulation and mayaffect vision and central nervous system function. A computed tomographyscan (CT scan) or a magnetic resonance imaging (MRI) scan is usually thefirst imaging test for a TIA, followed by carotid ultrasonography. Ifcarotid stenosis is identified, cerebral arteriography may be done.Treatment is aimed at preventing further TIAs and especially atpreventing a stroke. Aspirin or another antiplatelet drug is oftenchosen for drug therapy. Treatment with a statin is recommended for mostpeople after atherothromboembolic TIA. A timely endarterectomy forsevere carotid stenosis is likely to prevent future TIAs [JOHNSTON S C,Nguyen-Huynh M N, Schwarz M E, et al. National Stroke Associationguidelines for the management of transient ischemic attacks. Ann Neurol60(3, 2006):301-313; JOHNSTON SC, Rothwell P M, Nguyen-Huynh M N, GilesM F, Elkins J S, Bernstein A L, Sidney S. Validation and refinement ofscores to predict very early stroke risk after transient ischaemicattack. Lancet 369(9558, 2007):283-292].

Strokes and TIAs have similar risk factors, i.e. factors that increasethe likelihood of having a stroke and/or TIA. One of the mostsignificant of them is advancing age, such that the average age ofpatients affected by stroke is 70 years in men and 75 years in women.Nevertheless, strokes occur in a significant number of infants andchildren as well, the epidemiology of which is complicated by associatedhead injuries, infections, migraine headaches, hereditary disorders, andcerebrovascular dysfunction in general [ROACH E S, Golomb M R, Adams R,et al. Management of stroke in infants and children: a scientificstatement from a Special Writing Group of the American Heart AssociationStroke Council and the Council on Cardiovascular Disease in the Young.Stroke 39(9, 2008):2644-2691].

In addition to age, the following are considered to be primaryestablished risk factors for stroke in adults: current smoking, diabetesmellitus, systolic blood pressure, antihypertensive therapy, priorcoronary heart disease, left ventricular hypertrophy, and race. However,many other risk factors may be predictive as well, such as body massindex, waist:hip ratio, HDL cholesterol, albumin, von Willebrand factor,alcohol consumption, intima-media thickness, peripheral arterialdisease, infection and inflammation, recreational drugs and medications,mental stress, perturbations in systemic metabolism, acute increases inblood pressure, changes in blood coagulation, migraine headache, atrialfibrillation, and carotid stenosis [CHAMBLESS L E, Heiss G, Shahar E,Earp M J, Toole J. Prediction of ischemic stroke risk in theAtherosclerosis Risk in Communities Study. Am J Epidemiol 160(3,2004):259-269; MacCLELLAN L R, Giles W, Cole J, Wozniak M, Stern B,Mitchell BD, Kittner S J. Probable migraine with visual aura and risk ofischemic stroke: the stroke prevention in young women study. Stroke38(9, 2007):2438-2445; ELKIND MS. Why now? Moving from stroke riskfactors to stroke triggers. Curr Opin Neurol 20(1, 2007):51-57].

Traditional risk assessment using variables such as the ones describedin the previous paragraph treats the occurrence of stroke or a transientischemic attack as a random event, the probability of which is afunction of the risk-factor status of the patient. According to thatpoint of view, one prevents strokes in a probabilistic sense by takingsteps to develop more favorable risk factor values (e.g., diet change,smoking cessation, control diabetes or blood pressure with medicationsand/or lifestyle changes, or undergo a carotid endarterectomy or carotidstenting for patients with symptomatic carotid stenosis) [JOHNSEN SP,Overvad K, Stripp C, Tjønneland A, Husted SE, Sørensen HT. Intake offruit and vegetables and the risk of ischemic stroke in a cohort ofDanish men and women. Am J Clin Nutr 78(1, 2003):57-64]. Family historyof stroke is also an independent risk factor, suggesting the existenceof genetic factors that may interact with environmental factors [AhamedHASSAN and Hugh S. Markus. Genetics and ischaemic stroke. Brain 123(2000):1784-1812; patent application US20120021989, entitled Geneticmarkers for risk management of atrial fibrillation and stroke, to HOLMet al.]. Although genetic risk factors, which cannot be changed, mayalso contribute to the risk of stroke, knowledge of those factors maymotivate the patient to address other risk factors.

In a number of commonly assigned, co-pending applications, Applicantdisclosed the use of noninvasive vagus nerve stimulation to treat oravert some of conditions that may put the patient at risk for sufferinga stroke, particularly atrial fibrillation and migraine headache[US20130131746, entitled Non-invasive vagus nerve stimulation devicesand methods to treat or avert atrial fibrillation, to SIMON et al.;US20110276107, entitled Electrical and magnetic stimulators used totreat migraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, andcomorbid disorders, to SIMON et al]. Similarly, risk factors thatpromote the occurrence of stroke will secondarily promote the risk forvascular dementia, which may be caused by multiple mini-strokes[NYENHUIS D L, Gorelick P B. Vascular dementia: a contemporary review ofepidemiology, diagnosis, prevention, and treatment. J Am Geriatr Soc46(11, 1988):1437-1448; WANG J, Zhang H Y, Tang X C. Cholinergicdeficiency involved in vascular dementia: possible mechanism andstrategy of treatment. Acta Pharmacol Sin 30(7, 2009):879-888]. In acommonly assigned, co-pending application, Applicant disclosed the useof noninvasive vagus nerve stimulation to treat or avert dementia, sothe present application extends that disclosure [US 20130066392,entitled Non-invasive magnetic or electrical nerve stimulation to treator prevent dementia, to SIMON et al.] These applications are herebyincorporated by reference.

In another co-pending, commonly assigned application, US20130066395,entitled Nerve stimulation methods for averting imminent onset orepisode of a disease, to SIMON et al., Applicant disclosed a different,novel approach to preventing strokes, in which one endeavors to forecastthe actual onset of a stroke in an individual, seconds to minutes beforethe event, and then take prompt prophylactic countermeasures to avert,limit or ameliorate the stroke or TIA. The present application extendsthat disclosure. Such an approach would be particularly appropriate forindividuals who have had a recent TIA and are likely to suffer a strokein the next few days [JOHNSTON SC, Rothwell P M, Nguyen-Huynh M N, GilesM F, Elkins J S, Bernstein A L, Sidney S. Validation and refinement ofscores to predict very early stroke risk after transient ischaemicattack. Lancet 369(9558, 2007):283-292].

A stroke causes an infarct, which comprises irreversibly dead or dyingneuronal tissue that has been deprived of oxygen. The infarct issurrounded by a penumbra of ischemic tissue, which is salvagable withprompt restoration of oxygen through blood perfusion. Therefore, promptdiagnosis and treatment of the stroke patient is essential in order tosave as much of the penumbra tissue as possible, thereby saving theneuronal functions that are performed by that salvagable tissue.Ischemic stroke is generally painless, and the patient usually remainsconscious during the diagnosis. Neurological symptoms that are exhibitedby the patient upon interrogation and examination are used to make apreliminary evaluation as to whether a stroke has occurred.

During the evaluation, the clinician will attempt to determine themechanism of the stroke (if any), classifying it as having anindeterminate pathogenesis prior to imaging, an infarct, or ahemorrhage. The clinician will also attempt to determine the bloodvessels that are involved, classifying the stroke as a total anteriorcirculation stroke, a lacunar stroke, a partial anterior circulationstroke, or a posterior circulation stroke. For example, the middlecerebral artery is most commonly affected with the arm more severelyaffected than the leg. With anterior cerebral artery stroke, the leg ismore affected than the arm. Posterior cerebral strokes result inhomomynous hemianopsia. Basilar artery strokes are frequently associatedwith vertigo, diplopia, dysarthria or Horner syndrome, and hemiparesisis not a feature. Cerebral venous sinus thrombosis presents withsymptoms and signs of cerebral vascular disease with less discreteevidence of focal lesions. However, the accurate determination of strokesubtype eventually requires neuroimaging to distinguish ischemic fromhemorrhagic stroke [STAM J. Thrombosis of the cerebral veins andsinuses. N Engl J Med 352 (2005):1791-1798; THALER D E, Frosch M P. Caserecords of the Massachusetts General Hospital. Weeklyclinicopathological exercises. Case 16-2002. A 41-year-old woman withglobal headache and an intracranial mass. N Engl J Med 346(21,2002):1651-1658].

The diagnosis would also attempt to rule out conditions that mimicstroke, e.g., seizures, hypoglycemia, migraine with aura, hypertensiveencephalopathy, Wernicke's encephalopathy, CNS abscess, CNS tumor, ordrug toxicity [Goldstein L B, Simel DL. Is this patient having a stroke?JAMA 293 (2005):2391-2402; JAUCH E C, Saver J L, Adams HP Jr, et al.Guidelines for the early management of patients with acute ischemicstroke: a guideline for healthcare professionals from the American HeartAssociation/American Stroke Association. Stroke 44(3, 2013):870-894].

Several testing instruments are commonly used to assess stroke severityas part of the neurological examination of a suspected stroke patient.One such instrument is the NIH Stroke Scale, which involves quantitativeassessment of the patient's consciousness, eye movements, visual fields,facial palsy, arm movement, leg movement, coordination of musclemovement, tactile sensory loss, speech comprehension, speecharticulation, and attention to simultaneous bilateral stimulation [MEYERBC, Lyden P D. The modified National Institutes of Health Stroke Scale:its time has come. Int J Stroke 4(4, 2009):267-273].

Diagnostic tests are also performed in order to rule out other possiblediagnoses and aid in treatment selection, comprising: blood glucose,oxygen saturation, serum electrolytes/renal function tests, completeblood count, including platelet count, markers of cardiac ischemia,prothrombin time/INR, activated partial thromboplastin time, and ECG.Brain imaging, using noncontrast brain CT or brain MRI, then providesinvaluable information affecting the treatment decision, including thesize, location, and vascular distribution of the infarction, thepresence of bleeding, severity of ischemic stroke, and/or presence oflarge-vessel occlusion. Diffusion-weighted MRI imaging has emerged asthe most sensitive and specific technique for imaging an acute infarct.The imaging is preferably performed within 30 minutes of the patient'sarrival in an emergency room. Imaging tools are available for measuringthe tissue size, location, and topography of the stroke [KENNEDY D N,Haselgrove C, Makris N, Goldin D M, Lev M H, Caplan D, Caviness V S.WebParc: a tool for analysis of the topography and volume of stroke fromMRI. Med Biol Eng Comput 48(3, 2010):215-228]. However, such imaging mayproduce a false negative if it is performed too soon, so measurement ofthe patient's EEG may also be performed as a companion to the imaging,or in lieu of the imaging if CT or MRI imagers are not available. Theinformation from imaging and EEG are complementary—imaging ispredominantly anatomic and static, whereas EEG is predominantlyphysiologic and dynamic. [JORDAN KG. Emergency EEG and continuous EEGmonitoring in acute ischemic stroke. J Clin Neurophysiol 21(5,2004):341-352; FERREE T C, Hwa R C. Electrophysiological measures ofacute cerebral ischaemia. Phys Med Biol 50(17, 2005):3927-3939].

General supportive care and monitoring is then initiated in conjunctionwith the stroke therapy that is selected. The care and monitoringinvolves the measurement of oxygen saturation and provision ofsupplemental oxygen as required; measurement of body temperature andpossible induction of hypothermia for purposes of neuroprotection;cardiac monitoring to prevent arrhythmias; measurement of blood pressureand possible manipulation of the pressure to maintain some (but notexcessive) cerebral perfusion; correction of hypovolemia withintravenous normal saline; and an attempt to achieve normoglycemia ifblood glucose levels are abnormal.

It is impossible to know whether stroke symptoms are due to ischemia orhemorrhage based on clinical characteristics alone. Vomiting, systolicblood pressure greater than 220 mm Hg, severe headache, coma ordecreased level of consciousness, and progression over minutes or hoursall suggest intracerebral hemorrhage (ICH), although none of thesefindings are specific. Therefore, neuroimaging is mandatory to make thediagnosis. For patients with a hemorrhage, surgical treatment may beindicated. Patients with cerebellar hemorrhage who are deterioratingneurologically or who have brainstem compression and/or hydrocephalusfrom ventricular obstruction should undergo surgical removal of thehemorrhage as soon as possible. For patients presenting with lobarclots >30 mL and within 1 cm of the surface, evacuation ofsupratentorial ICH by standard craniotomy might be considered[MORGENSTERN L B, Hemphill J C 3rd, Anderson C, et al. Guidelines forthe management of spontaneous intracerebral hemorrhage: a guideline forhealthcare professionals from the American Heart Association/AmericanStroke Association. Stroke 41(9, 2010):2108-2129]. The clinicalpresentation of an aneurysmal subarachnoid hemorrhage (aSAH) is verydistinctive, namely, a headache characterized as being extremely suddenand immediately reaching maximal intensity (thunderclap headache).Surgical clipping or endovascular coiling of the ruptured aneurysmshould be performed as early as feasible in the majority of patients toreduce the rate of rebleeding after aSAH [CONNOLLY E S Jr, Rabinstein AA, Carhuapoma J R, et al. Guidelines for the management of aneurysmalsubarachnoid hemorrhage: a guideline for healthcare professionals fromthe American Heart Association/American Stroke Association. Stroke 43(6,2012):1711-1737].

Intravenous fibrinolytic (clot dissolving) therapy for acute stroke iscurrently the primary treatment for ischemic stroke, using intravenousrecombinant tissue plasminogen activator (rtPA) at 0.9 mg/kg with amaximum dose of 90 mg, over 60 minutes, with 10% of the dose given as abolus over 1 minute. The major risk of intravenous rtPA treatment issymptomatic intracranial hemorrhage (sICH). The fibrinolytic therapy ispreferably initiated within three hours of the stroke onset, and withinone hour after arrival in the emergency room, but the therapy may beuseful at up to 4.5 hours after onset of the stroke.

If intravenous fibrinolytic treatment is contraindicated in a patient,or if it does not produce the desired results, other treatment optionsare available. Endovascular treatment of ischemic stroke has increasedsubstantially over the past decade to include: (1) intra-arterialfibrinolysis, possibly in conjunction with intravenous fibrinolysis; (2)mechanical clot retrieval through mechanical embolectomy usingmicro-guidewires, micro-snares, retrievers and aspirators, such as theMERCI L5 device (Concentric Medical, Inc, Mountain View, Calif.) and thePenumbra System (Penumbra, Inc, Alameda, Calif.); and (3) acuteangioplasty and stenting, e.g., using the TREVO Retriever (ConcentricMedical, Inc, Mountain View, Calif.).

The use of thrombin inhibitors and certain anticoagulation therapy(heparin and the like) is not currently recommended. However, oraladministration of the antiplatelet agent aspirin (initial dose is 325mg) within 24 to 48 hours after stroke onset is recommended fortreatment of most patients.

Neuroprotective treatment of a stroke patient may also be attempted.Neuroprotection refers to using a therapy that directly affects thebrain tissue to salvage or delay the infarction of the still-viableischemic penumbra, rather than reperfusing the tissue. Neuroprotectivestrategies include antagonizing the effects of excitatory amino acids,such as glutamate, transmembrane fluxes of calcium, intracellularactivation of proteases, apoptosis, free radical damage, inflammation,and membrane damage. More than a thousand neuroprotective therapies havebeen proposed [O'COLLINS V E, Macleod M R, Donnan G A, Horky L L, vander Worp B H, Howells D W. 1,026 Experimental treatments in acutestroke. Ann Neurol 59 (2006):467-477; GINSBERG MD. Neuroprotection forischemic stroke: past, present and future. Neuropharmacology 55(2008):363-389; KIDWELL C S, Liebeskind D S, Starkman S, Saver J L.Trends in acute ischemic stroke trials through the 20th century. Stroke32 (2001):1349-1359]. These include the use of drugs that limit thecellular effects of acute ischemia or reperfusion (nimodipine,lubeluzole, clomethiazole, NXY-059, tirilazad, citicoline, enlimomab,cerebrolysin, statins, erythropoietin, magnesium, and even thecombination of caffeine and alcohol) [PIRIYAWAT P, Labiche L A, Burgin WS, Aronowski J A, Grotta JC. Pilot dose-escalation study of caffeineplus ethanol (caffeinol) in acute ischemic stroke. Stroke 34(2003):1242-1245].

Another treatment is the use of hypothermia, which has been shown to beneuroprotective in experimental and focal hypoxic brain injury models.An older neuroprotective strategy is the use of hyperbaric oxygen, butclinical data concerning its use are inconclusive, and some data implythat the intervention may be harmful. A relatively new neuroprotectivetreatment is the application of a near-infrared laser light to theshaved skull to selectively deliver energy to mitochondria in thedamaged region [YIP S, Zivin J. Laser therapy in acute stroke treatment.Int J Stroke 3 (2008):88-91].

Electrical stimulation of the vagus nerve has also been investigated asa neuroprotective treatment for stroke [MASADA T, Itano T, Fujisawa M,Miyamoto O, Tokuda M, Matsui H, Nagao S, Hatase O. Protective effect ofvagus nerve stimulation on forebrain ischaemia in gerbil hippocampus.Neuroreport 7(2, 1996):446-448]. In experiments by MIYAMOTO et al, theleft vagus nerve was exposed at the cervical level and attached toelectrodes. Transient global ischemia was induced for 5 minutes byocclusion of the bilateral common carotid arteries. The vagus nerve wasstimulated during ischemia using an electrical stimulator, with astrength of 0.4 mA, frequency of 40 Hz and duration of 1 ms. Thestimulation rescued approximately 50% of the hippocampal neurons fromthe ischemic insult [MIYAMOTO O, Pang J, Sumitani K, Negi T, HayashidaY, Itano T. Mechanisms of the anti-ischemic effect of vagus nervestimulation in the gerbil hippocampus. Neuroreport 14(15,2003):1971-1974].

In experiments by HIRAKI et al, the right vagus nerve of a rat wasstimulated, starting 30 minutes after proximal middle cerebral arteryocclusion, consisting of 30-second pulse trains (20 Hz) delivered to theanimal's right vagus nerve every 5 minutes for a total period of 60minutes. Stimulation of the vagus nerve was found to reduce the infarctsize by over 50% and provide neuroprotection for at least 3 weeks[HIRAKI T, Baker W, Greenberg J H. Effect of vagus nerve stimulationduring transient focal cerebral ischemia on chronic outcome in rats. JNeurosci Res 90(4, 2012):887-894].

In experiments performed by SUN et al, stimulating electrodes wereimplanted on the cervical part of the right vagus nerve, and electricalstimulation was initiated 30 minutes after the induction of ischemia anddelivered for 30 seconds every 5 minutes for 1 hour. The pulse trainsconsisted of 0.5 mA square pulses with width 0.3 milliseconds andrepetition rate of 20 Hz. Vagus nerve stimulation resulted in a 56.3%decrease in total infarct volume in transient middle cerebral arteryocclusion and a 38.4% decrease in permanent middle cerebral arteryocclusion [SUN Z, Baker W, Hiraki T, Greenberg J H. The effect of rightvagus nerve stimulation on focal cerebral ischemia: an experimentalstudy in the rat. Brain Stimul 5(1, 2012):1-10].

AI and colleagues implanted stimulating electrodes on the cervical partof the right vagus nerve. Electrical stimulation was initiated 30minutes after the induction of ischemia, and delivered for 30 seconds atevery 30 minutes for 3 hours in experimental group 1, and at every 5minutes for 1 hour in experimental group 2. Square pulses were deliveredat a constant current of 0.5 mA with a 30 second train of 0.5 ms pulsesdelivered at 20 Hz. In both cases, the vagal nerve stimulation reducedinfarct size by approximately half [AY I, Lu J, Ay H, Gregory SorensenA. Vagus nerve stimulation reduces infarct size in rat focal cerebralischemia. Neurosci Lett 459(3, 2009):147-151]. In a follow-upinvestigation, AI and colleagues showed that stimulation of vagus nerveexerts its infarct-reducing effect in the contralateral hemisphere, aswell as the ipsilateral hemisphere, such that unilateral vagus nervestimulation leads to alterations in both hemispheres. The protectivemechanism was found not to involve augmenting of cerebral blood flowunder ischemic conditions. The authors noted that several potentialmechanisms for the observed benefit are: suppression of increasedneuronal excitability, reduction of cytokine overproduction andinflammation, and activation of brain regions that are known to elicitneuroprotection upon activation [AY I, Sorensen A G, Ay H. Vagus nervestimulation reduces infarct size in rat focal cerebral ischemia: anunlikely role for cerebral blood flow. Brain Res 1392 (2011):110-115].

In these reports, AI et al note that the clinical relevance of suchfindings is limited because the stimulation methods are invasive. Otherinvestigators teach against performing even a noninvasive vagus nervestimulation at the neck as a protection against neuroinflammation. Thus,in patent application US20080249439, entitled Treatment of inflammationby non-invasive stimulation, to TRACEY et al., it is disclosed that: “Anexample of such undesirable manner/location is cervical massage of thevagus nerve, which is performed in a location adjacent to the carotidartery and/or carotid body (an organ responsible for monitoring arterialblood pressure). Although non-invasive stimulation at this location canbe effective for treating an inflammatory disorder, such stimulation mayraise the risk of stroke. Accordingly, the non-invasive stimulation maybe understood to mean excluding such regions.”

In the above-mentioned experiments, vagus nerve stimulation was the onlytreatment for acutely treating the stroke. But in patent application US20100004717, entitled Timing control for paired plasticity, to KILGARDet al, it is noted that anti-coagulants could be paired with vagus nervestimulation to act as clot busters during an acute stroke. Some of theabove-mentioned investigations attempted to elucidate the mechanism bywhich vagus nerve stimulation could produce its neuroprotective effectin stroke patients. Related investigations have attempted to elucidatethe mechanisms by which vagus nerve stimulation could produce aneuroprotective effect on traumatic brain injury patients, rather thanstroke patients [NEESE S L, Sherill L K, Tan A A, Roosevelt R W,Browning R A, Smith D C, Duke A, Clough R W. Vagus nerve stimulation mayprotect GABAergic neurons following traumatic brain injury in rats: Animmunocytochemical study. Brain Res 1128(1, 2007):157-163; BANSAL V, RyuS Y, Lopez N, Allexan S, Krzyzaniak M, Eliceiri B, Baird A, Coimbra R.Vagal stimulation modulates inflammation through a ghrelin mediatedmechanism in traumatic brain injury. Inflammation 35(1, 2012):214-220].

Yet other potential neuroprotective mechanisms have been discussed inconnection with experiments that involved the vagus nerve in strokepatients, but not its electrical stimulation [OTTANI A, Giuliani D,Mioni C, Galantucci M, Minutoli L, Bitto A, Altavilla D, Zaffe D,Botticelli A R, Squadrito F, Guarini S. Vagus nerve mediates theprotective effects of melanocortins against cerebral and systemic damageafter ischemic stroke. J Cereb Blood Flow Metab 29(3, 2009):512-523;MRAVEC B. The role of the vagus nerve in stroke. Auton Neurosci 158(1-2,2010):8-12; CHEYUO C, Jacob A, Wu R, Zhou M, Coppa G F, Wang P. Theparasympathetic nervous system in the quest for stroke therapeutics. JCereb Blood Flow Metab 31(5, 2011):1187-1195].

Once the thrombosis, arterial embolism, or hemorrhage has beeneliminated and the full extent of tissue damage within the patient'sbrain has developed, the medically stable patient then undergoesrehabilitation therapy with the objective of recovering function thatwas lost as a result of the stroke. Speech therapy is appropriate forstroke patients with aphasia, or with dysarthria and apraxia of speech.Occupational therapy is used to help the patient relearn activities ofdaily living such as eating, dressing, and toileting. Much of therehabilitation is directed to helping the patient regain motor skills,not only involving hands, arms and legs, but also involving muscles suchas those used to swallow [John YOUNG, Anne Forster. Rehabilitation afterstroke. BMJ 334 (2007):86-90; BATES B, Choi J Y, Duncan P W, Glasberg JJ, et al. Veterans Affairs/Department of Defense Clinical PracticeGuideline for the Management of Adult Stroke Rehabilitation Care:executive summary. Stroke 36(9, 2005):2049-2056; RODIN M, Saliba D,Brummel-Smith K et al. Guidelines abstracted from the Department ofVeterans Affairs/Department of Defense clinical practice guideline forthe management of stroke rehabilitation. J Am Geriatr Soc; 54(1,2006):158-162; KOLLEN B J, Lennon S, Lyons B, Wheatley-Smith L, ScheperM, Buurke J H, Halfens J, Geurts A C, Kwakkel G. The effectiveness ofthe Bobath concept in stroke rehabilitation: what is the evidence?Stroke 40(4, 2009):e89-e97; Naoyuki TAKEUCHI and Shin-Ichi Izumi.Rehabilitation with poststroke motor recovery: a review with a focus onneural plasticity. Stroke Research and Treatment Volume 2013, Article ID128641, pp. 1-13].

Magnetic stimulation is one treatment that has been used to help thepatient recover motor skills. However, such magnetic stimulation isapplied to the patient's cranium, not to the vagus nerve in thepatient's neck, and it resembles the use of transcranial direct currentstimulation in that regard [BOLOGNINI N, Pascual-Leone A, Fregni F.Using non-invasive brain stimulation to augment motor training-inducedplasticity. J Neuroeng Rehabil 6 (2009):8, pp. 1-13; TROMPETTO C, AssiniA, Buccolieri A, Marchese R, Abbruzzese G. Motor recovery followingstroke: a transcranial magnetic stimulation study. Clin Neurophysiol111(10, 2000):1860-1867; KHEDR E M, Ahmed M A, Fathy N, Rothwell JC.Therapeutic trial of repetitive transcranial magnetic stimulation afteracute ischemic stroke. Neurology 65(3, 2005):466-468; Anwen EVANS.Transcrianial magnetic stimulation and stroke: a review. The MagstimCompany Ltd, Spring Gardens, Whitland, Carmarthenshire, SA34 0HR, UnitedKingdom, 2008. pp. 1-29; CORTI M, Patten C, Triggs W. Repetitivetranscranial magnetic stimulation of motor cortex after stroke: afocused review. Am J Phys Med Rehabil 91(3, 2012):254-270; HSU W Y,Cheng C H, Liao K K, Lee I H, Lin Y Y. Effects of repetitivetranscranial magnetic stimulation on motor functions in patients withstroke: a meta-analysis. Stroke 43(7, 2012):1849-1857].

Complementary and alternative medicine interventions have also been usedto treat the symptoms of stroke. In a review of acupuncture treatmentbeginning up to one month after the stroke, beneficial effects could notbe ascertained. The acupuncture treatment points are ordinarily on thescalp and certain places on the body, but not in the vicinity of thevagus nerve on the neck [ZHANG S, Liu M, Asplund K, Li L. Acupuncturefor acute stroke. Cochrane Database of Systematic Reviews 2005, Issue 2.Art. No.: CD003317, pp. 1-37].

Electical stimulation of the patient's vagus nerve has been proposed asa treatment for the recovery of motor skills during strokerehabilitation. As described by KILGARD and colleagues, the vagus nervestimulation is applied simultaneously (paired) with patient movements[Patent application US20130041419, entitled Methods, systems, anddevices for pairing vagus nerve stimulation with motor therapy in strokepatients, to KILGARD et al.; PORTER B A, Khodaparast N, Fayyaz T, CheungR J, Ahmed S S, Vrana W A, Rennaker R L 2nd, Kilgard M P. Repeatedlypairing vagus nerve stimulation with a movement reorganizes primarymotor cortex. Cereb Cortex 22(10, 2012):2365-2374].

Spatial neglect is characterized by a failure to attend to, look at, andrespond to stimuli (objects, food, people) located on the side of thebody opposite to the side affected by the infarct [HEILMAN KM,Valenstein E, Watson RT. Neglect and related disorders. Semin Neurol20(4, 2000):463-470]. It is apparently due to damage or loss ofconnections within networks in the brain known as the dorsal and ventralattention networks [CORBETTA M, Kincade M J, Lewis C, Snyder A Z, SapirA. Neural basis and recovery of spatial attention deficits in spatialneglect. Nat Neurosci 8(11, 2005):1603-1610; CARTER AR, Astafiev S V,Lang C E, Connor L T, Rengachary J, Strube M J, Pope D L, Shulman G L,Corbetta M. Resting interhemispheric functional magnetic resonanceimaging connectivity predicts performance after stroke. Ann Neurol 67(3,2011):365-375; VERDON V, Schwartz S, Lovblad K O, Hauert C A,Vuilleumier P. Neuroanatomy of hemispatial neglect and its functionalcomponents: a study using voxel-based lesion-symptom mapping. Brain133(Pt 3, 2010):880-894].

Current treatment for spatial neglect consists of finding ways to bringthe patient's attention toward the inattentive side (usually left), doneincrementally, beginning a few degrees past midline [PIERCE SR, BuxbaumLJ. Treatments of unilateral neglect: a review. Arch Phys Med Rehabil83(2, 2002):256-268; LUAUTE J, Halligan P, Rode G, Rossetti Y, BoissonD. Visuo-spatial neglect: a systematic review of current interventionsand their effectiveness. Neurosci Biobehav Rev 30(7, 2006):961-982;BOWEN A, Lincoln NB. Cognitive rehabilitation for spatial neglectfollowing stroke. Cochrane Database Syst Rev (2, 2007):CD003586, pp.1-46]. Stimulation methods have been used to treat spatial neglect inpatients, consisting of galvanic vestibular stimulation, transcranialmagnetic stimulation and transcranial direct-current stimulation, butnot vagus nerve stimulation, much less noninvasive vagus nervestimulation [LIM JY, Kang E K, Paik N J. Repetitive transcranialmagnetic stimulation to hemispatial neglect in patients after stroke: anopen-label pilot study. J Rehabil Med 42(5, 2010):447-452]. All suchmethods have been concerned with the rehabilitation of a stroke patientwith spatial neglect. In contrast, the present invention also discloseslimiting the extent of potential spatial neglect by using vagus nervestimulation before or during the acute phase of the stroke. In thataspect of the invention, the therapy resembles the use of lightdeprivation to limit attentional deficits in traumatic brain injurypatients, wherein the light deprivation limits eventual attentionaldeficits, but not necessarily sensorimotor deficits [VARGO J M, GrachekR A, Rockswold G L. Light deprivation soon after frontal brain traumaaccelerates recovery from attentional deficits and promotes functionalnormalization of basal ganglia. J Trauma 47(2, 1999):265-272].

To summarize the foregoing background information, stroke and transientischemic attacks cause major medical and public health problems. Currentmethods for treating them are only partially successful, either acutelyor in the rehabilitative patient. Although animal experiments suggestthat treatment of a stroke in its acute phase using vagus nervestimulation may be neuroprotective, methods used in those experimentsare of limited utility because they are invasive.

SUMMARY OF THE INVENTION

The present invention involves devices and methods for the treatment orprevention of stroke and/or transient ischemic attacks. In certainaspects of the invention, a device or system comprises an energy sourceof magnetic and/or electrical energy that is transmitted to, or in closeproximity to, a selected nerve of the patient to temporarily stimulateand/or modulate the signals in the selected nerve. In preferredembodiments of the invention, the selected nerve is a vagus nerve in thepatient's neck.

In certain embodiments, the methods and devices that are disclosed hereare intended to make stimulation of the vagus nerve clinically useful,because they can be performed noninvasively. In other embodiments, thestimulation waveforms disclosed here are significantly different thanthe waveforms that have been used in the animal experiments.

Apart from the reduction of risk factors over the long term, there arecurrently no methods available for forecasting and averting an imminentstroke or transient ischemic attack, except for the methods disclosed inco-pending, commonly assigned application US20130066395, entitled Nervestimulation methods for averting imminent onset or episode of a disease,to SIMON et al. The present disclosure expands on those prophylacticmethods.

The present invention also discloses stimulation of the cervical vagusnerve, by electrical or magnetic stimulation of the cervical vagusnerve, as a method for helping the stroke patient recover motor skillsduring rehabilitation. Unlike the methods of KILGARD and colleagues, thepresently disclosed methods do not require a pairing of the stimulationwith motor movements. Instead, the therapeutic stimulation may takeplace between sessions of motor physical therapy rehabilitation.

The present invention also discloses use of noninvasive nervestimulation for the rehabilitative treatment of conditions other thanmotor deficits in stroke patients. In particular, noninvasive vagusnerve stimulation may be used to treat a condition known as spatialneglect, also known as hemispatial neglect, hemiagnosia, hemineglect,unilateral neglect, unilateral visual inattention, hemi-inattention orneglect syndrome. It is said to occur in approximately 25-30% of allstroke-affected individuals, although some estimates place the frequencyas high as 90% [RINGMAN J M, Saver J L, Woolson R F, Clarke W R, Adams HP. Frequency, risk factors, anatomy, and course of unilateral neglect inan acute stroke cohort. Neurology 63(3, 2004):468-474; BUXBAUM L J,Ferraro M K, Veramonti T, Frame A, Whyte J, Ladavas E, Frassinetti F,Coslett HB. Hemispatial neglect: Subtypes, neuroanatomy, and disability.Neurology 62(5, 2004):749-756; KLEINMAN JT, Newhart M, Davis C,Heidler-Gary J, Gottesman R F, Hillis AE. Right hemispatial neglect:frequency and characterization following acute left hemisphere stroke.Brain Cogn 64(1, 2007):50-59]. Spatial neglect occurs in stroke patientsof all ages, including children [LAURENT-VANNIER A, Pradat-Diehl P,Chevignard M, Abada G, De Agostini M. Spatial and motor neglect inchildren. Neurology 60(2, 2003):202-207].

In one aspect of the invention, noninvasive vagus nerve stimulation maybe used as a neuroprotective therapy during acute stroke, e.g., byacting in opposition to glutamate-mediated excitation of nerve tissue,through the inhibitory effects of GABA, and/or serotonin, and/ornorepinephrine that are released from the periaqueductal gray, raphenucei, and locus coeruleus, respectively.

The brain contains several neural networks that can be identified bybrain imaging, which are known as resting state networks. Examples ofsuch networks include the default mode network (DMN), the ventralattention network (VAN), the dorsal attention network (DAN), networksthat include the anterior insula (AI) and anterior cingulate cortex(ACC), and the sensory-motor network (SMN) comprising the somatosensory,premotor, and supplementary motor cortices. The locus ceruleus isthought to project to all of the resting state networks. Vagusstimulation methods of the present invention increase norepinephrinelevels in a resting state network, wherein a particular resting statenetwork may be preferentially stimulated via the locus ceruleus, byusing a vagus nerve stimulation waveform that entrains to the signatureEEG pattern of that network. Depending on the distribution of adrenergicreceptor subtypes within the resting state network, the vagus nervestimulation may deactivate or activate the network. Deactivation of aresting state network may also be accomplished by activating anotherresting state network, which causes deactivation of other networks.

Resting state networks may be abnormal in individuals with stroke and/ortransient ischemic attacks, which may be identified using fMRImeasurement. The measurements may point to abnormalities in particularnetworks such as networks related attention, salience, and theprocessing of sensory information; or in the sensory-motor network. Theymay also point to abnormalities in the switching or toggling betweennetworks. The present invention modulates the activity such restingstate networks via the locus ceruleus, by training an abnormal restingstate network to become more normal. For example, such training may beused to increase the activity of the sensory-motor network network orits subcomponents. It may also attempt to change the signature EEGpattern of a network, by slowly changing the frequency content of thestimulation & EEG pattern of the network to which the stimulator isentrained. The training may be accompanied by other modalities ofsensory stimulation or physical therapy.

Use of noninvasive vagus nerve stimulation to treat a stroke-relatedcondition known as spatial neglect is disclosed. The methods fortreating spatial neglect are useful not only during the rehabilitativephase of treatment, but also during acute stroke, so as to limit theeventual severity of spatial neglect in the patient.

A vagus nerve stimulation treatment according to the present inventionis conducted for thirty seconds to five minutes, preferably about 90seconds to about three minutes and more preferably about two minutes(each defined as a single dose). For prophylactic treatments, such as atreatment to avert a stroke or transient ischemic attack, the therapypreferably comprises multiple doses/day over a period of time that maylast from one week to a number of years. In certain embodiments, thetreatment will comprise multiple doses at predetermined times during theday and/or at predetermined intervals throughout the day. In exemplaryembodiments, the treatment comprises one of the following: (1) 3 singledoses/day at predetermined intervals or times; (2) two doses, eitherconsecutively, or separated by 5 min at predetermined intervals ortimes, preferably two or three times/day; (3) 3 doses, eitherconsecutively or separated by 5 min again at predetermined intervals ortimes, such as 2 or 3 times/day; or (4) 1-3 doses, either consecutivelyor separated by 5 min, 4-6 times per day. Initiation of a treatment maybegin when an imminent stroke or TIA is forecasted, or in a risk-factorreduction program it may be performed throughout the day beginning afterthe patient arises in the morning.

For an acute treatment, such as treatment of acute stroke, the therapymay consist of: (1) 1 treatment at the onset of symptoms; (2) 1treatment at the onset of symptoms, followed by another treatment at5-15 min; or (3) 1 treatment every hour.

For long term treatment of an acute insult such as one that occursduring the rehabilitation of a stroke patient, the therapy may consistof: (1) 3 treatments/day; (2) 2 treatments, either consecutively orseparated by 5 min, 3×/day; (3) 3 treatments, either consecutively orseparated by 5 min, 2×/day; (4) 2 or 3 treatments, either consecutivelyor separated by 5 min, up to 10×/day; or (5) 1, 2 or 3 treatments,either consecutively or separated by 5 min, every 15, 30, 60 or 120 min.In an exemplary embodiment, each treatment session comprises 1-3 dosesadministered to the patient either consecutively or separated by 5minutes. The treatment sessions are administered every 15, 30, 60 or 120minutes during the day such that the patient could receive 2 doses everyhour throughout a 24 hour day.

For all of the treatments listed above, one may alternate treatmentbetween left and right sides, or in the case of stroke or migraine thatoccur in particular brain hemispheres, one may treat ipsilateral orcontralateral to the stroke-hemisphere or headache side, respectively.Or for a single treatment, one may treat one minute on one side followedby one minute on the opposite side. Variations of these treatmentparadigms may be chosen on a patient-by-patient basis. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the symptoms of patients. Differentstimulation parameters may also be selected as the course of thepatient's condition changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

In one embodiment, the method of treatment includes positioning the coilof a magnetic stimulator non-invasively on or above a patient's neck andapplying a magnetically-induced electrical impulse non-invasively to thetarget region within the neck to stimulate or otherwise modulateselected nerve fibers. In another embodiment, surface electrodes areused to apply electrical impulses non-invasively to the target regionwithin the neck to likewise stimulate or otherwise modulate selectednerve fibers. Preferably, the target region is adjacent to, or in closeproximity with, the carotid sheath that contains a vagus nerve.

The non-invasive magnetic stimulator device is used to modulateelectrical activity of a vagus nerve, without actually introducing amagnetic field into the patient. The preferred stimulator comprises twotoroidal windings that lie side-by-side within separate stimulatorheads, wherein the toroidal windings are separated by electricallyinsulating material. Each toroid is in continuous contact with anelectrically conducting medium that extends from the patient's skin tothe toroid. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to 100 volts. The currentis passed through the coils in bursts of pulses, as described below,shaping an elongated electrical field of effect.

In another embodiment of the invention, the stimulator comprises asource of electrical power and two or more remote electrodes that areconfigured to stimulate a deep nerve. The stimulator may comprise twoelectrodes that lie side-by-side within a hand-held enclosure, whereinthe electrodes are separated by electrically insulating material. Eachelectrode is in continuous contact with an electrically conductingmedium that extends from the interface element of the stimulator to theelectrode. The interface element also contacts the patient's skin whenthe device is in operation.

Current passing through an electrode may be about 0 to about 40 mA, withvoltage across the electrodes of about 0 to about 30 volts. The currentis passed through the electrodes in bursts of pulses. There may be 1 to20 pulses per burst, preferably five pulses. Each pulse within a bursthas a duration of about 20 to about 1000 microseconds, preferably about200 microseconds. A burst followed by a silent inter-burst intervalrepeats at about 1 to 5000 bursts per second (bps, similar to Hz),preferably at about 15-50 bps, and even more preferably at about 25 bps.The preferred shape of each pulse is a full sinusoidal wave.

A source of power supplies a pulse of electric charge to the electrodesor magnetic stimulator coil, such that the electrodes or magneticstimulator produce an electric current and/or an electric field withinthe patient. The electrical or magnetic stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at about 1000 Hz. For example, the device mayproduce an electric field within the patient of about 10 to about 600V/m (preferably less than about 100 V/m) and an electrical fieldgradient of greater than about 2 V/m/mm. Electric fields that areproduced at the vagus nerve are generally sufficient to excite allmyelinated A and B fibers, but not necessarily the unmyelinated Cfibers. However, by using a reduced amplitude of stimulation, excitationof A-delta and B fibers may also be avoided.

The preferred stimulator shapes an elongated electric field of effectthat can be oriented parallel to a long nerve, such as a vagus. Byselecting a suitable waveform to stimulate the nerve, along withsuitable parameters such as current, voltage, pulse width, pulses perburst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves in theskin that produce pain.

Treating or averting stroke and/or transient ischemic attacks may beimplemented within the context of control theory. A controllercomprising, for example, one of the disclosed vagus nerve stimulators, aPID, and a feedforward model, provides input to the patient viastimulation of one or both of the patient's vagus nerves. Feedforwardmodels may be black box models, particularly models that make use ofsupport vector machines. Data for training and exercising the models arefrom noninvasive physiological and/or environmental signals obtainedfrom sensors located on or about the patient. A disclosed model predictsthe imminent onset of a stroke or transient ischemic attack. If thesymptoms are in progress, the vagus nerve stimulation may be used toameliorate or abort them.

The novel systems, devices and methods for treating stroke and/ortransient ischemic attacks are more completely described in thefollowing detailed description of the invention, with reference to thedrawings provided herewith, and in claims appended hereto. Otheraspects, features, advantages, etc. will become apparent to one skilledin the art when the description of the invention herein is taken inconjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1A shows structures within a patient's nervous system that may bemodulated by electrical stimulation of a vagus nerve.

FIG. 1B shows functional networks within the brain (resting statenetworks) that may be modulated by electrical stimulation of a vagusnerve.

FIG. 1C shows subcomponents of a resting state network that isresponsible for movements of a stroke patient, as well asinterconnections between those components.

FIG. 1D shows how interconnections between the subcomponents shown inFIG. 1C have changed in the stroke patient, relative to theinterconnections prior to the stroke.

FIG. 2A is a schematic view of an exemplary nerve modulating deviceaccording to the present invention which supplies controlled pulses ofelectrical current to a magnetic stimulator coil.

FIG. 2B is a schematic view of another embodiment of a nerve modulatingdevice according to the present invention which supplies electricalcurrent to surface electrodes.

FIG. 2C illustrates an exemplary electrical voltage/current profileaccording to the present invention.

FIG. 2D illustrates an exemplary waveform for stimulating and/ormodulating impulses that are applied to a nerve.

FIG. 2E illustrates another exemplary waveform for stimulating and/ormodulating impulses applied to a nerve.

FIG. 3A is a perspective view of the top of a dual-toroid magneticstimulator coil according to an embodiment of the present invention.

FIG. 3B is a perspective view of the bottom of the magnetic stimulatorcoil of FIG. 3A.

FIG. 3C is a cut-a-way view of the magnetic stimulator coil of FIG. 3A.

FIG. 3D is another cut-a-way view of the magnetic stimulator coil ofFIG. 3A.

FIG. 3E illustrates the magnetic stimulator coil of FIGS. 3A-3D attachedvia cable to a box containing the device's impulse generator, controlunit, and power source.

FIG. 4A is a perspective view of a dual-electrode stimulator accordingto another embodiment of the present invention.

FIG. 4B is a cut-a-way view of the dual-electrode stimulator of FIG. 4A.

FIG. 4C is an exploded view of one of the electrode assemblies of thedual-electrode stimulator of FIG. 4A.

FIG. 4D is a cut-a-way view of the electrode assembly of FIG. 4C.

FIG. 5A is perspective view of the top of an alternative embodiment ofthe dual-electrode stimulator of FIG. 4A.

FIG. 5B is a perspective view of the bottom of the dual-electrodestimulator of FIG. 5A.

FIG. 5C is a cut-a-way view of the dual-electrode stimulator of FIG. 5A.

FIG. 5D is another cut-a-way view of the dual-electrode stimulator ofFIG. 5.

FIG. 6A illustrates the approximate position of the housing of thestimulator according one embodiment of the present invention, when usedto stimulate the right vagus nerve in the neck of an adult patient.

FIG. 6B illustrates the approximate position for stimulation of a child.

FIG. 7 illustrates the housing of the stimulator according oneembodiment of the present invention, when positioned to stimulate avagus nerve in the patient's neck, wherein the stimulator is applied tothe surface of the neck in the vicinity of the identified anatomicalstructures.

FIG. 8 illustrates connections between the controller and controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one embodiment of the invention, a time-varying magnetic field,originating and confined to the outside of a patient, generates anelectromagnetic field and/or induces eddy currents within tissue of thepatient. In another embodiment, electrodes applied to the skin of thepatient generate currents within the tissue of the patient. An objectiveof the invention is to produce and apply the electrical impulses so asto interact with the signals of one or more nerves, in order to preventor avert a stroke and/or transient ischemic attack, to ameliorate orlimit the effects of an acute stroke or transient ischemic attack,and/or to rehabilitate a stroke patient.

Much of the disclosure will be directed specifically to treatment of apatient by electromagnetic stimulation in or around a vagus nerve, withdevices positioned non-invasively on or near a patient's neck. However,it will also be appreciated that the devices and methods of the presentinvention can be applied to other tissues and nerves of the body,including but not limited to other parasympathetic nerves, sympatheticnerves, spinal or cranial nerves. As recognized by those having skill inthe art, the methods should be carefully evaluated prior to use inpatients known to have preexisting cardiac issues.

In some embodiments, numbers expressing frequencies, periods of time, orquantities or levels of current, voltage, energy, and so forth, used todescribe and claim certain embodiments of the present disclosure are tobe understood as being modified in some instances by the term “about.”In some embodiments, the term “about” is used to indicate that a valueincludes the standard deviation of the mean for the device or methodbeing employed to determine the value. In some embodiments, thenumerical parameters set forth in the written description and attachedclaims are approximations that can vary depending upon the desiredproperties sought to be obtained by a particular embodiment. In someembodiments, the numerical parameters should be construed in light ofthe number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of some embodiments of thepresent disclosure are approximations, the numerical values set forth inthe specific examples are reported as precisely as practicable. Thenumerical values presented in some embodiments of the present disclosuremay contain certain errors necessarily resulting from the standarddeviation found in their respective testing measurements. The recitationof ranges of values herein is merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range. Unless otherwise indicated herein, each individual value isincorporated into the specification as if it were individually recitedherein.

FIG. 1A shows the location of the stimulation as “Vagus NerveStimulation,” relative to its connections with other anatomicalstructures that are potentially affected by the stimulation. Indifferent embodiments of the invention, various brain and brainstemstructures are preferentially modulated by the stimulation. Thesestructures will be described in sections of the disclosure that follow,along with the rationale for modulating their activity as a prophylaxisor treatment for stroke or transient ischemic attack. As a preliminarymatter, we first describe the vagus nerve itself and its most proximalconnections, which are particularly relevant to the disclosure below ofthe electrical waveforms that are used to perform the stimulation.

The vagus nerve (tenth cranial nerve, paired left and right) is composedof motor and sensory fibers. The vagus nerve leaves the cranium, passesdown the neck within the carotid sheath to the root of the neck, thenpasses to the chest and abdomen, where it contributes to the innervationof the viscera.

A vagus nerve in man consists of over 100,000 nerve fibers (axons),mostly organized into groups. The groups are contained within fasciclesof varying sizes, which branch and converge along the nerve. Undernormal physiological conditions, each fiber conducts electrical impulsesonly in one direction, which is defined to be the orthodromic direction,and which is opposite the antidromic direction. However, externalelectrical stimulation of the nerve may produce action potentials thatpropagate in orthodromic and antidromic directions. Besides efferentoutput fibers that convey signals to the various organs in the body fromthe central nervous system, the vagus nerve conveys sensory (afferent)information about the state of the body's organs back to the centralnervous system. Some 80-90% of the nerve fibers in the vagus nerve areafferent (sensory) nerves, communicating the state of the viscera to thecentral nervous system. Propagation of electrical signals in efferentand afferent directions are indicated by arrows in FIG. 1A. Ifcommunication between structures is bidirectional, this is shown in FIG.1A as a single connection with two arrows, rather than showing theefferent and afferent nerve fibers separately.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm). A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths. It is understood that the anatomy ofthe vagus nerve is developing in newborns and infants, which accounts inpart for the maturation of autonomic reflexes. Accordingly, it is alsounderstood that the parameters of vagus nerve stimulation in the presentinvention are chosen in such a way as to account for this age-relatedmaturation [PEREYRA P M, Zhang W, Schmidt M, Becker L E. Development ofmyelinated and unmyelinated fibers of human vagus nerve during the firstyear of life. J Neurol Sci 110(1-2, 1992):107-113; SCHECHTMAN VL, HarperR M, Kluge K A. Development of heart rate variation over the first 6months of life in normal infants. Pediat[Res 26(4, 1989):343-346].

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia. These ganglia take the form ofswellings found in the cervical aspect of the vagus nerve just caudal tothe skull. There are two such ganglia, termed the inferior and superiorvagal ganglia. They are also called the nodose and jugular ganglia,respectively (See FIG. 1A). The jugular (superior) ganglion is a smallganglion on the vagus nerve just as it passes through the jugularforamen at the base of the skull. The nodose (inferior) ganglion is aganglion on the vagus nerve located in the height of the transverseprocess of the first cervical vertebra.

Vagal afferents traverse the brainstem in the solitary tract, with someeighty percent of the terminating synapses being located in the nucleusof the tractus solitarius (or nucleus tractus solitarii, nucleus tractussolitarius, or NTS, see FIG. 1A). The NTS projects to a wide variety ofstructures in the central nervous system, such as the amygdala, raphenuclei, periaqueductal gray, nucleus paragigantocellurlais, olfactorytubercule, locus ceruleus, nucleus ambiguus and the hypothalamus. TheNTS also projects to the parabrachial nucleus, which in turn projects tothe hypothalamus, the thalamus, the amygdala, the anterior insula, andinfralimbic cortex, lateral prefrontal cortex, and other corticalregions [JEAN A. The nucleus tractus solitarius: neuroanatomic,neurochemical and functional aspects. Arch Int Physiol Biochim Biophys99(5, 1991):A3-A52]. Such central projections are discussed below inconnection with the interoception and resting state neural networks.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections (see FIG. 1A), controls parasympatheticfunction primarily below the level of the diaphragm (e.g. gut and itsenterochromaffin cells), while the ventral vagal complex, comprised ofnucleus ambiguus and nucleus retrofacial, controls functions primarilyabove the diaphragm in organs such as the heart, thymus and lungs, aswell as other glands and tissues of the neck and upper chest, andspecialized muscles such as those of the esophageal complex. Forexample, the cell bodies for the preganglionic parasympathetic vagalneurons that innervate the heart reside in the nucleus ambiguus, whichis relevant to potential cardiovascular side effects that may beproduced by vagus nerve stimulation.

With the foregoing as preliminary information about the vagus nerve, thetopics that are presented below in connection with the disclosure of theinvention include the following: (1) Overview of physiologicalmechanisms through which the disclosed vagus nerve stimulation methodsmay be used to modulate the neuronal circuitry of individuals at riskfor, or who have experienced, a stroke and/or transient ischemic attack;(2) Description of Applicant's magnetic and electrode-based nervestimulating devices, describing in particular the electrical waveformused to stimulate a vagus nerve; (3) Preferred embodiments of themagnetic stimulator; (4) Preferred embodiments of the electrode-basedstimulator; (5) Application of the stimulators to the neck of thepatient; (6) Use of the devices with feedback and feedforward to improvetreatment of individual patients.

Overview of physiological mechanisms through which the disclosed vagusnerve stimulation methods may be used to modulate the neuronal circuitryof individuals individuals at risk for, or who have suffered, a strokeand/or transient ischemic attack

We now disclose methods and devices for electrically stimulating a vagusnerve noninvasively, in order to provide medical treatment to anindividual at risk for, or who has suffered, a stroke and/or transientischemic attack. The disclosed methods and devices are an extension ofmethods and devices that have been developed for the treatment of otherconditions, as follows. Non-invasive stimulation of the cervical vagusnerve (nVNS) is a novel technology for treating various central nervoussystem disorders, primarily by stimulating specific afferent fibers ofthe vagus nerve to modulate brain function. This technology has beendemonstrated in animal and human studies to treat a wide range ofcentral nervous system disorders including headache (chronic and acutecluster and migraine), epilepsy, bronchoconstriction, anxiety disorders,depression, rhinitis, fibromyalgia, irritable bowel syndrome, stroke,traumatic brain injury, PTSD, Alzheimer's disease, autism, and others.Applicants have discovered that a two-minute stimulation has effectsthat may last up to 8 hours or longer depending on the type and severityof indication.

Broadly speaking, applicant has determined that there are threecomponents to the effects of nVNS on the brain. The strongest effectoccurs during the two minute stimulation and results in significantchanges in brain function that can be clearly seen as acute changes inautonomic function (e.g. measured using pupillometry, heart ratevariability, galvanic skin response, or evoked potential) and activationand inhibition of various brain regions as shown in fMRI imagingstudies. The second effect, of moderate intensity, lasts for 15 to 180minutes after stimulation. Animal studies have shown changes inneurotransmitter levels in various parts of the brain that persist forseveral hours. The third effect, of mild intensity, lasts up to 8 hoursand is responsible for the long lasting alleviation of symptoms seenclinically and, for example, in animal models of migraine headache.

Thus, depending on the medical indication, whether it is a chronic oracute treatment, and the natural history of the disease, differenttreatment protocols may be used. In particular, applicant has discoveredthat it is not necessary to “continuously stimulate” the vagus nerve (orto in order to provide clinically efficacious benefits to patients withcertain disorders. The term “continuously stimulate” as defined hereinmeans stimulation that follows a certain On/Off pattern continuously 24hours/day. For example, existing implantable vagal nerve stimulators“continuously stimulate” the vagus nerve with a pattern of 30 secondsON/5 minutes OFF (or the like) for 24 hours/day and seven days/week.Applicant has determined that this continuous stimulation is notnecessary to provide the desired clinical benefit for many disorders.For example, in the treatment of acute migraine attacks, the treatmentparadigm may comprise two minutes of stimulation at the onset of pain,followed by another two minute stimulation 15 minutes later. Forepilepsy, three 2 minute stimulations three times per day appear to beoptimal. Sometimes, multiple consecutive, two minute stimulations arerequired. Thus, the initial treatment protocol corresponds to what maybe optimum for the population of patients at large for a givencondition. However, the treatment may then be modified on anindividualized basis, depending on the response of each particularpatient.

The present invention contemplates three types of interventionsinvolving stimulation of a vagus nerve: prophylactic, acute andcompensatory (rehabilitative). Among these, the acute treatment involvesthe fewest administrations of vagus nerve stimulations, which begin uponthe appearance of symptoms. It is intended primarily to enlist andengage the autonomic nervous system to inhibit excitatoryneurotransmissions that accompany the symptoms. The prophylactictreatment resembles the acute treatment in the sense that it isadministered as though acute symptoms had just occurred (even thoughthey have not) and is repeated at regular intervals, as though thesymptoms were reoccurring (even though they are not). The rehabilitativeor compensatory treatments, on the other hand, seek to promote long-termadjustments in the central nervous system, compensating for deficienciesthat arose as the result of the patient's disease by making new neuralcircuits.

A vagus nerve stimulation treatment according to the present inventionis conducted for continuous period of thirty seconds to five minutes,preferably about 90 seconds to about three minutes and more preferablyabout two minutes (each defined as a single dose). After a dose has beencompleted, the therapy is stopped for a period of time (depending on thetreatment as described below). For prophylactic treatments, such as atreatment to avert a stroke or transient ischemic attack, the therapypreferably comprises multiple doses/day over a period of time that maylast from one week to a number of years. In certain embodiments, thetreatment will comprise multiple doses at predetermined times during theday and/or at predetermined intervals throughout the day. In exemplaryembodiments, the treatment comprises one of the following: (1) 3doses/day at predetermined intervals or times; (2) two doses, eitherconsecutively, or separated by 5 min at predetermined intervals ortimes, preferably two or three times/day; (3) 3 doses, eitherconsecutively or separated by 5 min again at predetermined intervals ortimes, such as 2 or 3 times/day; or (4) 1-3 doses, either consecutivelyor separated by 5 min, 4-6 times per day. Initiation of a treatment maybegin when an imminent stroke or TIA is forecasted, or in a risk-factorreduction program it may be performed throughout the day beginning afterthe patient arises in the morning.

For certain disorders, the time of day can be more important than thetime interval between treatments. For example, the locus correleus hasperiods of time during a 24 hour day wherein it has inactive periods andactive periods. Typically, the inactive periods can occur in the lateafternoon or in the middle of the night when the patient is asleep. Itis during the inactive periods that the levels of inhibitioryneurotransmitters in the brain that are generated by the locus correleusare reduced. This may have an impact on certain disorders. For example,patients suffering from migraines or cluster headaches often receivethese headaches after an inactive period of the locus correleus. Forthese types of disorders, the prophylactic treatment is optimal duringthe inactive periods such that the amounts of inhibitoryneurotransmitters in the brain can remain at a higher enough level tomitigate or abort an acute attack of the disorder.

In these embodiments, the prophlatic treatment may comprise multipledoses/day timed for periods of inactivity of the locus correleus. In oneembodiment, a treatment according to the present invention comprises oneor more doses administered 2-3 times per day or 2-3 “treatment sessions”per day. The treatment sessions preferably occur during the lateafternoon or late evening, in the middle of the night and again in themorning when the patient wakes up. In an exemplary embodiment, eachtreatment session comprises 1-4 doses, preferably 2-3 doses, with eachdose lasting for about 90 seconds to about three minutes.

For other disorders, the intervals between treatment sessions may be themost important as applicant has determined that stimulation of the vagusnerve can have a prolonged effect on the inhibitor neurotransmitterslevels in the brain, e.g., at least one hour, up to 3 hours andsometimes up to 8 hours. In one embodiment, a treatment according to thepresent invention comprises one or more doses (i.e., treatment sessions)administered at intervals during a 24 hour period. In a preferredembodiment, there are 1-5 such treatment sessions, preferably 2-4treatment sessions. Each treatment session preferably comprises 1-3doses, each lasting between about 60 seconds to about three minutes,preferably about 90 seconds to about 150 seconds, more preferably about2 minutes.

For an acute treatment, such as treatment of acute stroke, the therapyaccording to the present invention may comprise one or more embodiments:(1) 1 dose at the onset of symptoms; (2) 1 dose at the onset ofsymptoms, followed by another dose at 5-15 min; or (3) 1 dose every 15minutes to 1 hour at the onset of symptoms until the acute attack hasbeen mitigated or aborted. In these embodiments, each dose preferablylast between about 60 seconds to about three minutes, preferably about90 seconds to about 150 seconds, more preferably about 2 minutes.

For long term treatment of an acute insult such as one that occursduring the rehabilitation of a stroke patient, the therapy may consistof: (1) 3 treatments/day; (2) 2 treatments, either consecutively orseparated by 5 min, 3×/day; (3) 3 treatments, either consecutively orseparated by 5 min, 2×/day; (4) 2 or 3 treatments, either consecutivelyor separated by 5 min, up to 10×/day; or (5) 1, 2 or 3 treatments,either consecutively or separated by 5 min, every 15, 30, 60 or 120 min.In an exemplary embodiment, each treatment session comprises 1-3 dosesadministered to the patient either consecutively or separated by 5minutes. The treatment sessions are administered every 15, 30, 60 or 120minutes during the day such that the patient could receive 2 doses everyhour throughout a 24 hour day.

For all of the treatments listed above, one may alternate treatmentbetween left and right sides, or in the case of stroke or migraine thatoccur in particular brain hemispheres, one may treat ipsilateral orcontralateral to the stroke-hemisphere or headache side, respectively.Or for a single treatment, one may treat one minute on one side followedby one minute on the opposite side. Variations of these treatmentparadigms may be chosen on a patient-by-patient basis. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the symptoms of patients. Differentstimulation parameters may also be selected as the course of thepatient's condition changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

The prophylactic treatments may be most effective when the patient is ina prodromal, high-risk bistable state. In that state, the patient issimultaneously able to remain normal or exhibit symptoms, and theselection between normal and symptomatic states depends on theamplification of fluctuations by physiological feedback networks. Forexample, a thrombus may exist in either a gel or fluid phase, with thefeedback amplification of fluctuations driving the change of phaseand/or the volume of the gel phase. Thus, a thrombus may form or not,depending on the nonlinear dynamics exhibited by the network of enzymesinvolved in clot formation, as influenced by blood flow and inflammationthat may be modulated by vagus nerve stimulation [PANTELEEV MA,Balandina A N, Lipets E N, Ovanesov M V, Ataullakhanov F I.Task-oriented modular decomposition of biological networks: triggermechanism in blood coagulation. Biophys J 98(9, 2010):1751-1761; AlexeyM SHIBEKO, Ekaterina S Lobanova, Mikhail A Panteleev and Fazoil IAtaullakhanov. Blood flow controls coagulation onset via the positivefeedback of factor VII activation by factor Xa. BMC Syst Biol 2010; 4(2010):5, pp. 1-12]. Consequently, the mechanisms of vagus nervestimulation treatment during prophylaxis for a stroke are generallydifferent than what occurs during an acute treatment, when thestimulation inhibits excitatory neurotransmission that follows the onsetof ischemia that is already caused by the thrombus. Nevertheless, theprophylactic treatment may also inhibit excitatory neurotransmission soas to limit the excitation that would eventually occur upon formation ofa thrombus, and the acute treatment may prevent the formation of anotherthrombus.

The circuits involved in such inhibition are illustrated in FIG. 1A.Excitatory nerves within the dorsal vagal complex generally useglutamate as their neurotransmitter. To inhibit neurotransmission withinthe dorsal vagal complex, the present invention makes use of thebidirectional connections that the nucleus of the solitary tract (NTS)has with structures that produce inhibitory neurotransmitters, or itmakes use of connections that the NTS has with the hypothalamus, whichin turn projects to structures that produce inhibitoryneurotransmitters. The inhibition is produced as the result of thestimulation waveforms that are described below. Thus, acting inopposition to glutamate-mediated activation by the NTS of the areapostrema and dorsal motor nucleus are: GABA, and/or serotonin, and/ornorepinephrine from the periaqueductal gray, raphe nucei, and locuscoeruleus, respectively. FIG. 1A shows how those excitatory andinhibitory influences combine to modulate the output of the dorsal motornucleus. Similar influences combine within the NTS itself, and thecombined inhibitory influences on the NTS and dorsal motor nucleusproduce a general inhibitory effect.

The activation of inhibitory circuits in the periaqueductal gray, raphenucei, and locus coeruleus by the hypothalamus or NTS may also causecircuits connecting each of these structures to modulate one another.Thus, the periaqueductal gray communicates with the raphe nuclei andwith the locus coeruleus, and the locus coeruleus communicates with theraphe nuclei, as shown in FIG. 1A [PUDOVKINA OL, Cremers T I, WesterinkB H. The interaction between the locus coeruleus and dorsal raphenucleus studied with dual-probe microdialysis. Eur J Pharmacol 7(2002);445(1-2):37-42.; REICHLING D B, Basbaum A I. Collateralization ofperiaqueductal gray neurons to forebrain or diencephalon and to themedullary nucleus raphe magnus in the rat. Neuroscience 42(1,1991):183-200; BEHBEHANI M M. The role of acetylcholine in the functionof the nucleus raphe magnus and in the interaction of this nucleus withthe periaqueductal gray. Brain Res 252(2, 1982):299-307]. Theperiaqueductal gray, raphe nucei, and locus coeruleus also project tomany other sites within the brain, including those that would be excitedduring ischemia. Therefore, in this aspect of the invention, vagus nervestimulation during acute stroke or transient ischemic attack has ageneral neuroprotective, inhibitory effect via its activation of theperiaqueductal gray, raphe nucei, and locus coeruleus.

In particular, the vagus nerve stimulation may be neuroprotective to apart of the brain known as the insula (also known as the insularycortex, insular cortex, or insular lobe) and its connections with theanterior cingulate cortex (ACC). Neural circuits leading from the vagusnerve to the insula and ACC are shown in FIG. 1A. Protection of theinsula is particularly important for stroke patients, because damage tothe insula is known to cause symptoms that are typical in strokepatients, involving motor control, hand and eye motor movement, motorlearning, swallowing, speech articulation, the capacity for long andcomplex spoken sentences, sensation, and autonomic functions [ANDERSONTJ, Jenkins I H, Brooks D J, Hawken M B, Frackowiak R S, Kennard C.Cortical control of saccades and fixation in man. A PET study. Brain117(5, 1994):1073-1084; FINK GR, Frackowiak R S, Pietrzyk U, PassinghamRE (April 1997). Multiple nonprimary motor areas in the human cortex. J.Neurophysiol 77 (4, 1997): 2164-2174; SOROS P, Inamoto Y, Martin RE.Functional brain imaging of swallowing: an activation likelihoodestimation meta-analysis. Hum Brain Mapp 30(8, 2009):2426-2439; DRONKERSNF. A new brain region for coordinating speech articulation. Nature 384(6605, 1996): 159-161; ACKERMANN H, Riecker A. The contribution of theinsula to motor aspects of speech production: a review and a hypothesis.Brain Lang 89 (2, 2004): 320-328; BOROVSKY A, Saygin A P, Bates E,Dronkers N. Lesion correlates of conversational speech productiondeficits. Neuropsychologia 45 (11, 2007): 2525-2533; OPPENHEIMER S M,Kedem G, Martin WM. Left-insular cortex lesions perturb cardiacautonomic tone in humans. Clin Auton Res; 6(3, 1996):131-140; CRITCHLEYHD. Neural mechanisms of autonomic, affective, and cognitiveintegration. J. Comp. Neurol. 493 (1, 2005): 154-166].

Stroke patients with an infarct in the insula are particularlysusceptible to expansion of the infarct to surrounding tissue, so prompttreatment of such patients is important [AY H, Arsava E M, Koroshetz WJ, Sorensen A G. Middle cerebral artery infarcts encompassing the insulaare more prone to growth. Stroke 39(2, 2008):373-378]

In another embodiment of the invention, vagus nerve stimulation is usedto modulate the activity of particular neural networks known as restingstate networks, which are thought to become abnormal in individualsfollowing a stroke and/or transient ischemic attack. This embodiment ofthe invention is directed primarily to rehabilitative or compensatorytreatment. A neural network in the brain is accompanied by oscillationswithin the network. Low frequency oscillations are likely associatedwith connectivity at the largest scale of the network, while higherfrequencies are exhibited by smaller sub-networks within the largernetwork, which may be modulated by activity in the slower oscillatinglarger network. The default network, also called the default modenetwork (DMN), default state network, or task-negative network, is onesuch network that is characterized by coherent neuronal oscillations ata rate lower than 0.1 Hz. Other large scale networks also have thisslow-wave property, as described below [BUCKNER R L, Andrews-Hanna J R,Schacter D L. The brain's default network: anatomy, function, andrelevance to disease. Ann N Y Acad Sci 1124 (2008):1-38; PALVA J M,Palva S. Infra-slow fluctuations in electrophysiological recordings,blood-oxygenation-level-dependent signals, and psychophysical timeseries. Neuroimage 62(4, 2012):2201-2211; STEYN-ROSS ML, Steyn-Ross D A,Sleigh J W, Wilson M T. A mechanism for ultra-slow oscillations in thecortical default network. Bull Math Biol 73(2, 2011):398-416].

The default mode network corresponds to task-independent introspection(e.g., daydreaming), or self-referential thought. When the DMN isactivated, the individual is ordinarily awake and alert, but the DMN mayalso be active during the early stages of sleep and during conscioussedation. During goal-oriented activity, the DMN is deactivated and oneor more of several other networks, so-called task-positive networks(TPN), are activated. DMN activity is attenuated rather thanextinguished during the transition between states, and is observed,albeit at lower levels, alongside task-specific activations. Strength ofthe DMN deactivation appears to be inversely related to the extent towhich the task is demanding. Thus, DMN has been described as atask-negative network, given the apparent antagonism between itsactivation and task performance. The posterior cingulate cortex (PCC)and adjacent precuneus and the medial prefrontal cortex (mPFC) are thetwo most clearly delineated regions within the DMN [RAICHLE ME, Snyder AZ. A default mode of brain function: a brief history of an evolvingidea. Neuroimage 37(4, 2007):1083-1090; BROYD S J, Demanuele C, DebenerS, Helps S K, James C J, Sonuga-Barke E J. Default-mode braindysfunction in mental disorders: a systematic review. Neurosci BiobehavRev 33(3, 2009):279-96; BUCKNER R L, Andrews-Hanna J R, Schacter D L.The brain's default network: anatomy, function, and relevance todisease. Ann N Y Acad Sci 1124 (2008):1-38; BUCKNER R L, Sepulcre J,Talukdar T, Krienen F M, Liu H, Hedden T, Andrews-Hanna J R, Sperling RA, Johnson K A. Cortical hubs revealed by intrinsic functionalconnectivity: mapping, assessment of stability, and relation toAlzheimer's disease. J Neurosci 29 (2009):1860-1873; GREICIUS M D,Krasnow B, Reiss A L, Menon V. Functional connectivity in the restingbrain: a network analysis of the default mode hypothesis. Proc Natl AcadSci USA 100 (2003): 253-258].

The term low frequency resting state networks (LFRSN or simply RSN) isused to describe both the task-positive and task-negative networks.Using independent component analysis (ICA) and related methods to assesscoherence of fMRI Blood Oxygenation Level Dependent Imaging (BOLD)signals in terms of temporal and spatial variation, as well asvariations between individuals, low frequency resting state networks inaddition to the DMN have been identified, corresponding to differenttasks or states of mind. They are related to their underlying anatomicalconnectivity and replay at rest the patterns of functional activationevoked by the behavioral tasks. That is to say, brain regions that arecommonly recruited during a task are anatomically connected and maintainin the resting state (in the absence of any stimulation) a significantdegree of temporal coherence in their spontaneous activity, which iswhat allows them to be identified at rest [SMITH S M, Fox P T, Miller KL, Glahn D C, Fox P M, et al. Correspondence of the brain's functionalarchitecture during activation and rest. Proc Natl Acad Sci USA 106(2009): 13040-13045].

Frequently reported resting state networks (RSNs), in addition to thedefault mode network, include the sensorimotor RSN, the executivecontrol RSN, up to three visual RSNs, two lateralized fronto-parietalRSNs, the auditory RSN and the temporo-parietal RSN. However, differentinvestigators use different methods to identify the low frequencyresting state networks, so different numbers and somewhat differentidentities of RSNs are reported by different investigators [COLE DM,Smith S M, Beckmann CF. Advances and pitfalls in the analysis andinterpretation of resting-state FMRI data. Front Syst Neurosci 4(2010):8, pp. 1-15]. Examples of RSNs are described in publicationscited by COLE and the following: ROSAZZA C, Minati L. Resting-statebrain networks: literature review and clinical applications. Neurol Sci32(5, 2011):773-85; ZHANG D, Raichle M E. Disease and the brain's darkenergy. Nat Rev Neurol 6(1, 2010):15-28; DAMOISEAUX, J. S., Rombouts, S.A. R. B., Barkhof, F., Scheltens, P., Stam, C. J., Smith, S. M.,Beckmann, C.F. Consistent resting-state networks across healthysubjects. Proc. Natl. Acad. Sci. U.S.A. 103 (2006): 13848-13853 FOX MD,Snyder A Z, Vincent J L, Corbetta M, Van Essen D C, Raichle M E. Thehuman brain is intrinsically organized into dynamic, anticorrelatedfunctional networks. Proc Natl Acad Sci USA 102 (2005):9673-9678; LI R,Wu X, Chen K, Fleisher A S, Reiman E M, Yao L. Alterations ofDirectional Connectivity among Resting-State Networks in AlzheimerDisease. AJNR Am J Neuroradiol. 2012 Jul. 12. [Epub ahead of print, pp.1-6].

For example, the dorsal attention network (DAN) and ventral attentionnetwork (VAN) are two networks responsible for attentional processing.The VAN is involved in involuntary actions and exhibits increasedactivity upon detection of salient targets, especially when they appearin unexpected locations (bottom-up activity, e.g. when an automobiledriver unexpectedly senses a hazard or unexpected situation). The DAN isinvolved in voluntary (top-down) orienting and increases activity afterpresentation of cues indicating where, when, or to what individualsshould direct their attention [FOX MD, Corbetta M, Snyder A Z, Vincent JL, Raichle M E. Spontaneous neuronal activity distinguishes human dorsaland ventral attention systems. Proc Natl Acad Sci USA 103(2006):10046-10051; WEN X, Yao L, Liu Y, Ding M. Causal interactions inattention networks predict behavioral performance. J Neurosci 32(4,2012):1284-1292]. The DAN is bilaterally centered in the intraparietalsulcus and the frontal eye field. The VAN is largely right lateralizedin the temporal-parietal junction and the ventral frontal cortex.

The attention systems (e.g., VAN and DAN) have been investigated longbefore their identification as resting state networks, and functionsattributed to the VAN have in the past been attributed to the locusceruleus/noradrenaline system [ASTON-JONES G, Cohen JD. An integrativetheory of locus coeruleus-norepinephrine function: adaptive gain andoptimal performance. Annu Rev Neurosci 28 (2005):403-50; BOURET S, SaraS J. Network reset: a simplified overarching theory of locus coeruleusnoradrenaline function. Trends Neurosci 28(11, 2005):574-82; SARA S J,Bouret S. Orienting and Reorienting: The Locus Coeruleus MediatesCognition through Arousal. Neuron 76(1, 2012):130-41; BERRIDGE C W,Waterhouse B D. The locus coeruleus-noradrenergic system: modulation ofbehavioral state and state-dependent cognitive processes. Brain ResBrain Res Rev 42(1, 2003):33-84].

The attention systems originally described by PETERSON and Posner aremore expansive than just the VAN and DAN system, with interactinganatomical components corresponding to alerting, orienting, andexecutive control [PETERSEN SE, Posner M I. The attention system of thehuman brain: 20 years after. Annu Rev Neurosci 35 (2012):73-89]. In thatdescription, DAN and VAN comprise significant portions of the orientingsystem, and components largely involving locus ceruleus-norepinephrinefunction comprise the alerting system. Other resting state networks areinvolved with executive control [BECKMANN C F, DeLuca M, Devlin J T,Smith S M. Investigations into resting-state connectivity usingindependent component analysis. Philos Trans R Soc Lond B Biol Sci360(1457, 2005)1001-1013].

MENON and colleagues describe the anterior insula as being at the heartof the ventral attention system [ECKERT M A, Menon V, Walczak A,Ahlstrom J, Denslow S, Horwitz A, Dubno JR. At the heart of the ventralattention system: the right anterior insula. Hum Brain Mapp 30(8,2009):2530-2541; MENON V, Uddin L Q. Saliency, switching, attention andcontrol: a network model of insula function. Brain Struct Funct 214(5-6,2010):655-667]. However, SEELEY and colleagues used region-of-interestand independent component analyses of resting-state fMRI data todemonstrate the existence of an independent brain network comprised ofboth the anterior insula and dorsal ACC, along with subcorticalstructures including the amygdala, substantia nigra/ventral tegmentalarea, and thalamus. This network is distinct from the otherwell-characterized large-scale brain networks, e.g. the default modenetwork [SEELEY WW, Menon V, Schatzberg A F, Keller J, Glover G H, KennaH, et al. Dissociable intrinsic connectivity networks for salienceprocessing and executive control. J Neurosci 2007; 27(9):2349-2356].CAUDA and colleagues found that the human insula is functionallyinvolved in two distinct neural networks: i) the anterior pattern isrelated to the ventralmost anterior insula, and is connected to therostral anterior cingulate cortex, the middle and inferior frontalcortex, and the temporoparietal cortex; ii) the posterior pattern isassociated with the dorsal posterior insula, and is connected to thedorsal-posterior cingulate, sensorimotor, premotor, supplementary motor,temporal cortex, and to some occipital areas [CAUDA F, D'Agata F, SaccoK, Duca S, Geminiani G, Vercelli A. Functional connectivity of theinsula in the resting brain. Neuroimage 55(1, 2011):8-23; CAUDA F,Vercelli A. How many clusters in the insular cortex? Cereb Cortex. 2012Sep. 30. (Epub ahead of print, pp. 1-2)]. TAYLOR and colleagues alsoreport two such resting networks [TAYLOR K S, Seminowicz D A, Davis K D.Two systems of resting state connectivity between the insula andcingulate cortex. Hum Brain Mapp 30(9, 2009):2731-2745]. DEEN andcolleagues found three such resting state networks [DEEN B, Pitskel N B,Pelphrey K A. Three systems of insular functional connectivityidentified with cluster analysis. Cereb Cortex 21(7, 2011):1498-1506].

Damage to resting state networks may affect the stroke patient indifferent ways, one of which (so-called spatial neglect) involvesnetworks containing the patient's insula. It is particularly amenable totreatment by the disclosed methods. Spatial neglect (also known ashemispatial neglect, hemiagnosia, hemineglect, unilateral neglect,unilateral visual inattention, hemi-inattention or neglect syndrome)occurs in about 25-30% of all stroke-affected individuals. It ischaracterized by a failure to attend to, look at, and respond to stimuli(objects, food, people) located on the side of the body opposite to theside affected by the infarct [KLEINMAN JT, Newhart M, Davis C,Heidler-Gary J, Gottesman R F, Hillis AE. Right hemispatial neglect:frequency and characterization following acute left hemisphere stroke.Brain Cogn 64(1, 2007):50-59; BOWEN A, Lincoln NB. Cognitiverehabilitation for spatial neglect following stroke. Cochrane DatabaseSyst Rev. (2, 2007):CD003586, pp. 1-46]. Spatial neglect is apparentlydue to damage or loss of connections to the dorsal and ventral attentionnetworks (DAN and VAN) containing the insula [CORBETTA M, Kincade M J,Lewis C, Snyder A Z, Sapir A. Neural basis and recovery of spatialattention deficits in spatial neglect. Nat Neurosci 8(11,2005):1603-1610; CARTER A R, Astafiev S V, Lang C E, Connor L T,Rengachary J, Strube M J, Pope D L, Shulman G L, Corbetta M. Restinginterhemispheric functional magnetic resonance imaging connectivitypredicts performance after stroke. Ann Neurol 67(3, 2011):365-375;ECKERT MA, Menon V, Walczak A, Ahlstrom J, Denslow S, Horwitz A, DubnoJR. At the heart of the ventral attention system: the right anteriorinsula. Hum Brain Mapp 30(8, 2009):2530-2541; MENON V, Uddin L Q.Saliency, switching, attention and control: a network model of insulafunction. Brain Struct Funct 214(5-6, 2010):655-667].

Before disclosing methods for modulating resting state networks usingvagal nerve stimulation, we first discuss how stimulation of the vagusnerve can affect some of the relevant components of the brain, such asthe insula (see FIG. 1A). These structures are involved in thehigher-level processing of sensory information. The sensory informationconsists not only of hearing, vision, taste & smell, and touch, but alsoother sensory modalities such as proprioception, nociception andinteroception [SULLIVAN J E, Hedman L D. Sensory dysfunction followingstroke: incidence, significance, examination, and intervention. TopStroke Rehabil 15(3, 2008):200-217].

For purposes of illustration in FIG. 1A, we use interoceptive neuralpathways leading to the insula [CRAIG AD. How do you feel—now? Theanterior insula and human awareness. Nat Rev Neurosci 10(1,2009):59-70]. Anatomically, interoceptive sensations are distinguishedfrom surface touch (tactile) sensations by their association with thespinothalamic projection that ascend in the contralateral spinal cord,rather than with the dorsal column/medial lemniscal system which ascendsthe ipsilateral spinal cord. However, both contralateral and ipsilateralcircuits are shown in the spinal cord in FIG. 1A to indicate that thediscussion applies more generally to sensory processing, not just theinteroception that is used for purposes of discussion.

Many neural circuits that are involved in interoception are located inhigher regions of the central nervous system, but the invention cannevertheless electrically stimulate the vagus nerve in such a way as tomodulate the activity of those neural circuits. They are shown in ofFIG. 1A and described in paragraphs that follow [CRAIG AD. How do youfeel? Interoception: the sense of the physiological condition of thebody. Nat Rev Neurosci 3(8, 2002):655-666; BIELEFELDT K, Christianson JA, Davis B M. Basic and clinical aspects of visceral sensation:transmission in the CNS. Neurogastroenterol Motil 17(4, 2005):488-499;MAYER EA, Naliboff B D, Craig A D. Neuroimaging of the brain-gut axis:from basic understanding to treatment of functional GI disorders.Gastroenterology 131(6, 2006):1925-1942].

Interoceptive sensations arise from signals sent by parasympathetic andsympathetic afferent nerves. The latter are considered to be the primaryculprit for pain and other unpleasant emotional feelings, butparasympathetic afferents also contribute. Among afferents whose cellbodies are found in the dorsal root ganglia, the ones having type B cellbodies are most significant, which terminate in lamina I of the spinaland trigeminal dorsal horns. Other afferent nerves that terminate in thedeep dorsal horn provide signals related to mechanoreceptive,proprioceptive and nociceptive activity.

Lamina I neurons project to many locations. First, they project to thesympathetic regions in the intermediomedial and intermediolateral cellcolumns of the thoracolumbar cord, where the sympathetic preganglioniccells of the autonomic nervous system originate (See FIG. 1A). Second,in the medulla, lamina I neurons project to the A1 catecholaminergiccell groups of the ventrolateral medulla and then to sites in therostral ventrolateral medulla (RVLM) which is interconnected with thesympathetic neurons that project to spinal levels. Only a limited numberof discrete regions within the supraspinal central nervous systemproject to sympathetic preganglionic neurons in the intermediolateralcolumn (see FIG. 1A). The most important of these regions are therostral ventral lateral medulla (RVLM), the rostral ventromedial medulla(RVMM), the midline raphe, the paraventricular nucleus (PVN) of thehypothalamus, the medullocervical caudal pressor area (mCPA), and the A5cell group of the pons. The first four of these connections to theintermediolateral nucleus are shown in FIG. 1A [STRACK A M, Sawyer W B,Hughes J H, Platt K B, Loewy A D. A general pattern of CNS innervationof the sympathetic outflow demonstrated by transneuronal pseudorabiesviral infections. Brain Res. 491(1, 1989): 156-162].

The rostral ventral lateral medulla (RVLM) is the primary regulator ofthe sympathetic nervous system, sending excitatory fibers(glutamatergic) to the sympathetic preganglionic neurons located in theintermediolateral nucleus of the spinal cord. Vagal afferents synapse inthe NTS, and their projections reach the RVLM via the caudalventrolateral medulla. However, resting sympathetic tone also comes fromsources above the pons, from hypothalamic nuclei, various hindbrain andmidbrain structures, as well as the forebrain and cerebellum, whichsynapse in the RVLM. Only the hypothalamic projection to the RVLM isshown in FIG. 1A.

The RVLM shares its role as a primary regulator of the sympatheticnervous system with the rostral ventromedial medulla (RVMM) andmedullary raphe. Differences in function between the RVLM versusRVMM/medullary raphe have been elucidated for cardiovascular control,but are not well characterized for gastrointestinal control.Differential control of the RVLM by the hypothalamus may also occur viacirculating hormones such as vasopressin. The RVMM contains at leastthree populations of nitric oxide synthase neurons that send axons toinnervate functionally similar sites in the NTS and nucleus ambiguus.Circuits connecting the RVMM and RVLM may be secondary, via the NTS andhypothalamus.

In the medulla, lamina I neurons also project another site, namely, tothe A2 cell group of the nucleus of the solitary tract, which alsoreceives direct parasympathetic (vagal and glossopharyngeal) afferentinput. As indicated above, the nucleus of the solitary tract projects tomany locations, including the parabrachial nucleus. In the pons andmesencephalon, lamina I neurons project to the periaqueductal grey(PAG), the main homeostatic brainstem motor site, and to theparabrachial nucleus. Sympathetic and parasympathetic afferent activityis integrated in the parabrachial nucleus. It in turn projects to theinsular cortex by way of the ventromedial thalamic nucleus (VMb, alsoknown as VPMpc). A direct projection from lamina I to the ventromedialnucleus (VMpo), and a direct projection from the nucleus tractussolitarius to the VMb, provide a rostrocaudally contiguous column thatrepresents all contralateral homeostatic afferent input. They projecttopographically to the mid/posterior dorsal insula (See FIG. 1A).

In humans, this cortical image is re-represented in the anterior insulaon the same side of the brain. The parasympathetic activity isre-represented in the left (dominant) hemisphere, whereas thesympathetic activity is re-represented in the right (non-dominant)hemisphere. These re-representations provide the foundation for asubjective evaluation of interoceptive state, which is forwarded to theorbitofrontal cortex (See FIG. 1A).

The right anterior insula is associated with subjective awareness ofhomeostatic emotions (e.g., visceral and somatic pain, temperature,sexual arousal, hunger, and thirst) as well as all emotions (e.g.,anger, fear, disgust, sadness, happiness, trust, love, empathy, socialexclusion). This region is intimately interconnected with the anteriorcingulate cortex (ACC). Unpleasant sensations are directly correlatedwith ACC activation [KLIT H, Finnerup N B, Jensen T S. Centralpost-stroke pain: clinical characteristics, pathophysiology, and

management. Lancet Neurol 8(9, 2009):857-868]. The anterior cingulatecortex and insula are both strongly interconnected with theorbitofrontal cortex, amygdala, hypothalamus, and brainstem homeostaticregions, of which only a few connections are shown in FIG. 1A.

Methods of the present invention comprise modulation of resting statenetworks containing the insula using vagus nerve stimulation. A firstmethod directly targets the front end of the interoceptive pathwaysshown in FIG. 1A (nucleus tractus solitarius, area postrema, and dorsalmotor nucleus). The second method targets the distal end of theinteroceptive pathways (anterior insula and anterior cingulate cortex).

According to the first method, electrical stimulation of A and B fibersalone of a vagus nerve causes increased inhibitory neurotransmitters inthe brainstem, which in turn inhibits signals sent to the parabrachialnucleus, VMb and VMpo. The stimulation uses special devices and aspecial waveform (described below), which minimize effects involving Cfibers that might produce unwanted side-effects. The electricalstimulation first affects the dorsal vagal complex, which is the majortermination site of vagal afferent nerve fibers. The dorsal vagalcomplex consists of the area postrema (AP), the nucleus of the solitarytract (NTS) and the dorsal motor nucleus of the vagus. The AP projectsto the NTS and dorsal motor nucleus of the vagus bilaterally. It alsoprojects bilaterally to the parabrachial nucleus and receives directafferent input from the vagus nerve. Thus, the area postrema is in aunique position to receive and modulate ascending interoceptiveinformation and to influence autonomic outflow [PRICE CJ, Hoyda T D,Ferguson AV. The area postrema: a brain monitor and integrator ofsystemic autonomic state. Neuroscientist 14(2, 2008):182-194].

Projections to and from the locus ceruleus are particularly significantin the present invention because they are also used in the second methodthat is described below. The vagus nerve transmits information to thelocus ceruleus via the nucleus tractus solitarius (NTS), which has adirect projection to the dendritic region of the locus ceruleus. Otherafferents to, and efferents from, the locus ceruleus are described bySARA et al, SAMUELS et al, and ASTON-JONES [SARA S J, Bouret S.Orienting and Reorienting: The Locus Coeruleus Mediates Cognitionthrough Arousal. Neuron 76(1, 2012):130-41; SAMUELS ER, Szabadi E.Functional neuroanatomy of the noradrenergic locus coeruleus: its rolesin the regulation of arousal and autonomic function part I: principlesof functional organisation. Curr Neuropharmacol 6(3):235-53; SAMUELS, E.R., and Szabadi, E. Functional neuroanatomy of the noradrenergic locuscoeruleus: its roles in the regulation of arousal and autonomic functionpart II: physiological and pharmacological manipulations andpathological alterations of locus coeruleus activity in humans. Curr.Neuropharmacol. 6 (2008), 254-285; Gary ASTON-JONES. Norepinephrine.Chapter 4 (pp. 47-57) in: Neuropsychopharmacology: The Fifth Generationof Progress (Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, CharlesNemeroff, eds.) Philadelphia: Lippincott Williams & Wilkins, 2002].

In addition to the NTS, the locus ceruleus receives input from thenucleus gigantocellularis and its neighboring nucleusparagigantocellularis, the prepositus hypoglossal nucleus, theparaventricular nucleus of the hypothalamus, Barrington's nucleus, thecentral nucleus of the amygdala, and prefrontal areas of the cortex.These same nuclei receive input from the NTS, such that stimulation ofthe vagus nerve may modulate the locus ceruleus via the NTS and asubsequent relay through these structures.

The locus ceruleus has widespread projections throughout the cortex[SAMUELS ER, Szabadi E. Functional neuroanatomy of the noradrenergiclocus coeruleus: its roles in the regulation of arousal and autonomicfunction part I: principles of functional organisation. CurrNeuropharmacol 6 (3):235-53]. It also projects to subcortical regions,notably the raphe nuclei, which release serotonin to the rest of thebrain. An increased dorsal raphe nucleus firing rate is thought to besecondary to an initial increased locus ceruleus firing rate from vagusnerve stimulation [Adrienne E. DORR and Guy Debonnelv. Effect of vagusnerve stimulation on serotonergic and noradrenergic transmission. JPharmacol Exp Ther 318(2, 2006):890-898; MANTA S, Dong J, Debonnel G,Blier P. Enhancement of the function of rat serotonin and norepinephrineneurons by sustained vagus nerve stimulation. J Psychiatry Neurosci34(4, 2009):272-80]. The locus ceruleus also has projections toautonomic nuclei, including the dorsal motor nucleus of the vagus, asshown in FIG. 1A [FUKUDA, A., Minami, T., Nabekura, J., Oomura, Y. Theeffects of noradrenaline on neurones in the rat dorsal motor nucleus ofthe vagus, in vitro. J. Physiol., 393 (1987): 213-231; MARTINEZ-PENA yValenzuela, I., Rogers, R. C., Hermann, G. E., Travagli, R. A. (2004)Norepinephrine effects on identified neurons of the rat dorsal motornucleus of the vagus. Am. J. Physiol. Gas-trointest. Liver Physiol.,286, G333-G339; TERHORST, G. J., Toes, G. J., Van Willigen, J. D. Locuscoeruleus projections to the dorsal motor vagus nucleus in the rat.Neuroscience, 45 (1991): 153-160].

The circuits shown in FIG. 1A can be rerepresented in terms offunctional resting state networks that contain various components thatare shown in FIG. 1A. A simplified representation of those networks isshown in FIG. 1B. For purposes of discussion, we adopt the set ofresting state networks identified by LI et al, with the understandingthat according to the above-cited publications, a more or less detailedset could also be adopted [LI R, Wu X, Chen K, Fleisher A S, Reiman E M,Yao L. Alterations of Directional Connectivity among Resting-StateNetworks in Alzheimer Disease. AJNR Am J. Neuroradiol. 2012 Jul. 12.[Epub ahead of print, pp. 1-6]. A similar set of resting state networksis described by DING et al [DING JR, Liao W, Zhang Z, Mantini D, Xu Q,Wu G R, Lu G, Chen H. Topological fractionation of resting-statenetworks. PLoS One 6(10, 2011):e26596, pp. 1-9]. FIG. 1B also showsconnections between the networks, with the larger arrows indicatingstronger connections. Solid and dashed arrows are, respectively, forpositive and negative connections.

The resting state networks shown in FIG. 1B are as follows. Thedefault-mode network (DMN) includes the posterior cingulate, medialprefronta and bilateral inferior parietal cortices, and the medialtemporal lobe structures. The self-referential network (SRN) includesregions from the medial-ventral prefrontal cortex, the anteriorcingulate, and the posterior cingulate. Previous investigators includedthe SRN in the DMN.

As described above, the dorsal attention network (DAN) and ventralattention network (VAN) are two networks responsible for attentionalprocessing. The VAN is involved in involuntary actions and exhibitsincreased activity upon detection of salient targets, especially whenthey appear in unexpected locations (bottom-up activity, e.g. when anautomobile driver unexpectedly senses a hazard). The DAN is involved involuntary (top-down) orienting and increases activity after presentationof cues indicating where, when, or to what individuals should directtheir attention [FOX MD, Corbetta M, Snyder A Z, Vincent J L, Raichle ME. Spontaneous neuronal activity distinguishes human dorsal and ventralattention systems. Proc Natl Acad Sci USA 103 (2006):10046-10051; WEN X,Yao L, Liu Y, Ding M. Causal interactions in attention networks predictbehavioral performance. J Neurosci 32(4, 2012):1284-1292]. The DAN isbilaterally centered in the intraparietal sulcus and the frontal eyefield. The VAN is largely right lateralized in the temporal-parietaljunction and the ventral frontal cortex.

The sensory-motor network (SMN) is the network covering thesomatosensory, premotor, and supplementary motor cortices. This networkis described in more detail below and in FIGS. 1C and 1D for strokepatients. The lateral visual network (LVN) and medial visual network(MVN) are two networks for visual processing and are respectivelylocated in the lateral and medial parts of the visual cortex. Theauditory network (AN) is responsible for auditory processing and islocated in the bilateral superior temporal gyrus and in the primary andsecondary auditory cortices. The LVN, MVN, AN, and SMN are four networksrelated to sensory processing, and the DMN, SRN, DAN, and VAN areassociated with higher cognitive function.

The present invention modulates the activity of these resting statenetworks via the locus ceruleus by electrically stimulating the vagusnerve, as indicated in FIG. 1B. Stimulation of a network by that routemay activate or deactivate a resting state network, depending on thedetailed configuration of adrenergic receptor subtypes within thenetwork and their roles in enhancing or depressing neural activitywithin the network, as well as subsequent network-to-networkinteractions.

According to the invention, one key to preferential stimulation of aparticular resting state network, such as those involving the insula, isto use a vagus nerve stimulation signal that entrains to the signatureEEG pattern of that network (see below and MANTINI D, Perrucci M G, DelGratta C, Romani G L, Corbetta M. Electrophysiological signatures ofresting state networks in the human brain. Proc Natl Acad Sci USA104(32, 2007):13170-13175). By this EEG entrainment method, it may bepossible to preferentially attenuate or deactivate particular networks,such as DAN or VAN. Activation of another network such as the SMN, VANor DMN may also produce the same effect, via network-to-networkinteractions. Although the locus ceruleus is presumed to project to allof the resting networks, it is thought to project most strongly to theventral attention network (VAN) [CORBETTA M, Patel G, Shulman GL. Thereorienting system of the human brain: from environment to theory ofmind. Neuron 58(3, 2008):306-24; MANTINI D, Corbetta M, Perrucci M G,Romani G L, Del Gratta C. Large-scale brain networks account forsustained and transient activity during target detection. Neuroimage44(1, 2009):265-274]. Thus, deactivation of a particular network mayalso be attempted by activating another resting state network, becausethe brain switches between them.

Although all of the resting state networks may be affected by a stroke,the sensorimotor network (SMN) has been most intensely investigated instroke patients because of its role in controlling movements of thepatient, which may become abnormal and debilitating as the result of thestroke. Thus, in the acute phase of a stroke, over two-thirds ofpatients present with motor symptoms such as (hemi-)paresis or loss ofdexterity. Accordingly, the present invention also contemplatesstimulation of the SMN [JAMES G A, Lu Z L, VanMeter J W, Sathian K, Hu XP, Butler A J. Changes in resting state effective connectivity in themotor network following rehabilitation of upper extremity poststrokeparesis. Top Stroke Rehabil 16(4, 2009):270-281; PARK CH, Chang W H, OhnS H, Kim S T, Bang O Y, Pascual-Leone A, Kim Y H. Longitudinal changesof resting-state functional connectivity during motor recovery afterstroke. Stroke 42(5, 2011):1357-1362; GREFKES C, Fink G R.Reorganization of cerebral networks after stroke: new insights fromneuroimaging with connectivity approaches. Brain 134(Pt 5,2011):1264-1276; WARD N. Assessment of cortical reorganisation for handfunction after stroke. J Physiol 589(Pt 23, 2011):5625-5632; VANMEER MP, Otte W M, van der Marel K, Nijboer C H, Kavelaars A, van der SprenkelJ W, Viergever M A, Dijkhuizen R M. Extent of bilateral neuronal networkreorganization and functional recovery in relation to stroke severity. JNeurosci 32(13, 2012):4495-4507; WESTLAKE K P, Hinkley L B, Bucci M,Guggisberg A G, Byl N, Findlay A M, Henry R G, Nagarajan S S. Restingstate a-band functional connectivity and recovery after stroke. ExpNeurol 237(1, 2012):160-169; YIN D, Song F, Xu D, Peterson B S, Sun L,Men W, Yan X, Fan M. Patterns in cortical connectivity for determiningoutcomes in hand function after subcortical stroke. PLoS One 7(12,2012):e52727, pp. 1-10; JIANG L, Xu H, Yu C. Brain connectivityplasticity in the motor network after ischemic stroke. Neural Plast.2013; 2013:924192, pp. 1-11].

The SMN comprises motor-sensory-related regions such as the primarysensorimotor cortex, premotor cortex, supplementary motor area (SMA),cingulate motor area, secondary somatosensory cortex, cerebellum, basalganglia, thalamus, frontal and parietal cortices, and striate andextrastriate cortices. Movement is produced through the interaction ofcomponents of the SMN. The primary motor cortex, which is important involuntary movement, is located in the frontal lobes along the centralsulcus. Higher order motor areas (supplementary and premotor), which areinvolved in planning a movement, are located adjacent to the primarymotor cortex. The primary somatic sensory cortex is located in theparietal lobe along the central sulcus, and sensory signals from thebody surface are mapped to it for use in motor reflexes. The BasalGanglia is a collection of cell bodies that are interconnected and lienext to and on the lateral (outer) side of the thalamus and the ventral(inner) side of the white matter of the cerebral cortex. Structures thatmake up the basal ganglia include: caudate, putamen, nucleus accumbens,globus pallidus, substantia nigra, and the subthalamic nucleus of thethalamus. The basal ganglia is generally concerned with the coordinationof movement, in which the function of the basal ganglia is generallyinhibitory. The cerebellum provides excitatory inputs that are involvedin coordinating movement, balance and motor learning.

FIG. 1C shows exemplary connections between components of the SMN in apatient who has suffered a stroke. Components shown there are:cerebellum (Cereb), primary motor cortex (M1), prefrontal cortex (PFC),lateral premotor cortex (PMC), supplementary motor area (SMA), superiorparietal cortex (SPC) and thalamus (Thal). As also shown there, thecomponents are paired within the brain, and the components in the lefthalf of the figure represent the ones in the brain hemisphere that areaffected by the stroke. FIG. 1D shows increases and decreases inexcitatory and inhibitory interactions among these components, relativeto connections in the SMN prior to the stroke. As in FIG. 1C, componentsin the left half of the figure are the ones in the brain hemisphere thatare affected by the stroke [REHME A K, Grefkes C. Cerebral networkdisorders after stroke: evidence from imaging-based connectivityanalyses of active and resting brain states in humans. J Physiol 591(Pt1, 2013):17-31; INMAN CS, James G A, Hamann S, Rajendra J K, Pagnoni G,Butler A J. Altered resting-state effective connectivity offronto-parietal motor control systems on the primary motor networkfollowing stroke. Neuroimage 59(1, 2012):227-237].

It is understood that additional SMA components are involved inspecialized muscle movements. For example, the components most involvedin the loss and recovery of speech following a stroke are thesupplementary motor area (SMA, see FIGS. 1C and 1D) and its interactionwith the right Broca-homologue (not shown) [SAUR D, Lange R,Baumgaertner A, Schraknepper V, Willmes K, Rijntjes M, Weiller C.Dynamics of language reorganization after stroke. Brain 129(2006)1371-1384].

Description of Preferred Embodiments of Magnetic and Electrode-BasedNerve Stimulating/Modulating Devices

Devices of the invention that are used to stimulate a vagus nerve willnow be described. Either a magnetic stimulation device or anelectrode-based device may be used for that purpose. FIG. 2A is aschematic diagram of Applicant's magnetic nerve stimulating/modulatingdevice 301 for delivering impulses of energy to nerves for the treatmentof medical conditions. As shown, device 301 may include an impulsegenerator 310; a power source 320 coupled to the impulse generator 310;a control unit 330 in communication with the impulse generator 310 andcoupled to the power source 320; and a magnetic stimulator coil 341coupled via wires to impulse generator coil 310. The stimulator coil 341is toroidal in shape, due to its winding around a toroid of corematerial.

Although the magnetic stimulator coil 341 is shown in FIG. 2A to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 341 that is shown in FIG. 2Arepresents all the magnetic stimulator coils of the device collectively.In a preferred embodiment that is discussed below, coil 341 actuallycontains two coils that may be connected either in series or in parallelto the impulse generator 310.

The item labeled in FIG. 2A as 351 is a volume, surrounding the coil341, that is filled with electrically conducting medium. As shown, themedium not only encloses the magnetic stimulator coil, but is alsodeformable such that it is form-fitting when applied to the surface ofthe body. Thus, the sinuousness or curvature shown at the outer surfaceof the electrically conducting medium 351 corresponds also tosinuousness or curvature on the surface of the body, against which theconducting medium 351 is applied, so as to make the medium and bodysurface contiguous. As time-varying electrical current is passed throughthe coil 341, a magnetic field is produced, but because the coil windingis toroidal, the magnetic field is spatially restricted to the interiorof the toroid. An electric field and eddy currents are also produced.The electric field extends beyond the toroidal space and into thepatient's body, causing electrical currents and stimulation within thepatient. The volume 351 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 341 that is needed to accomplish stimulation of thepatient's nerve or tissue. In a preferred embodiment of the magneticstimulator that is discussed below, the conducting medium with which thecoil 341 is in contact need not completely surround the toroid.

The design of the magnetic stimulator 301, which is also adapted hereinfor use with surface electrodes, makes it possible to shape the electricfield that is used to selectively stimulate a relatively deep nerve suchas a vagus nerve in the patient's neck. Furthermore, the design producessignificantly less pain or discomfort (if any) to a patient, at the siteof stimulation on the skin, than stimulator devices that are currentlyknown in the art. Conversely, for a given amount of pain or discomforton the part of the patient (e.g., the threshold at which such discomfortor pain begins), the design achieves a greater depth of penetration ofthe stimulus under the skin.

An alternate embodiment of the present invention is shown in FIG. 2B,which is a schematic diagram of an electrode-based nervestimulating/modulating device 302 for delivering impulses of energy tonerves for the treatment of medical conditions. As shown, device 302 mayinclude an impulse generator 310; a power source 320 coupled to theimpulse generator 310; a control unit 330 in communication with theimpulse generator 310 and coupled to the power source 320; andelectrodes 340 coupled via wires 345 to impulse generator 310. In apreferred embodiment, the same impulse generator 310, power source 320,and control unit 330 may be used for either the magnetic stimulator 301or the electrode-based stimulator 302, allowing the user to changeparameter settings depending on whether coils 341 or the electrodes 340are attached.

Although a pair of electrodes 340 is shown in FIG. 2B, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 2Brepresent all electrodes of the device collectively.

The item labeled in FIG. 2B as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asdescribed below in connection with particular embodiments of theinvention, conducting medium in which the electrode 340 is embedded neednot completely surround an electrode. As also described below inconnection with a preferred embodiment, the volume 350 is electricallyconnected to the patient at a target skin surface in order to shape thecurrent density passed through an electrode 340 that is needed toaccomplish stimulation of the patient's nerve or tissue. The electricalconnection to the patient's skin surface is through an interface 351. Inone embodiment, the interface is made of an electrically insulating(dielectric) material, such as a thin sheet of Mylar. In that case,electrical coupling of the stimulator to the patient is capacitive. Inother embodiments, the interface comprises electrically conductingmaterial, such as the electrically conducting medium 350 itself, or anelectrically conducting or permeable membrane. In that case, electricalcoupling of the stimulator to the patient is ohmic. As shown, theinterface may be deformable such that it is form-fitting when applied tothe surface of the body. Thus, the sinuousness or curvature shown at theouter surface of the interface 351 corresponds also to sinuousness orcurvature on the surface of the body, against which the interface 351 isapplied, so as to make the interface and body surface contiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the coil 341 or electrodes 340. It is noted that nervestimulating/modulating device 301 or 302 may be referred to by itsfunction as a pulse generator. Patent application publicationsUS2005/0075701 and US2005/0075702, both to SHAFER, contain descriptionsof pulse generators that may be applicable to the present invention. Byway of example, a pulse generator is also commercially available, suchas Agilent 33522A Function/Arbitrary Waveform Generator, AgilentTechnologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard, computer mouse, andtouchscreen, as well as any externally supplied physiological signals(see FIG. 8), analog-to-digital converters for digitizing externallysupplied analog signals (see FIG. 8), communication devices for thetransmission and receipt of data to and from external devices such asprinters and modems that comprise part of the system, hardware forgenerating the display of information on monitors that comprise part ofthe system, and busses to interconnect the above-mentioned components.Thus, the user may operate the system by typing instructions for thecontrol unit 330 at a device such as a keyboard and view the results ona device such as the system's computer monitor, or direct the results toa printer, modem, and/or storage disk. Control of the system may bebased upon feedback measured from externally supplied physiological orenvironmental signals. Alternatively, the control unit 330 may have acompact and simple structure, for example, wherein the user may operatethe system using only an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes or coils, as well as the spatialdistribution of the electric field that is produced by the electrodes orcoils. The rise time and peak energy are governed by the electricalcharacteristics of the stimulator and electrodes or coils, as well as bythe anatomy of the region of current flow within the patient. In oneembodiment of the invention, pulse parameters are set in such as way asto account for the detailed anatomy surrounding the nerve that is beingstimulated [Bartosz SAWICKI, Robert Szmurto, Przemystaw Ptonecki, JacekStarzynski, Stanislaw Wincenciak, Andrzej Rysz. Mathematical Modellingof Vagus Nerve Stimulation. pp. 92-97 in: Krawczyk, A. ElectromagneticField, Health and Environment: Proceedings of EHE'07. Amsterdam, 105Press, 2008]. Pulses may be monophasic, biphasic or polyphasic.Embodiments of the invention include those that are fixed frequency,where each pulse in a train has the same inter-stimulus interval, andthose that have modulated frequency, where the intervals between eachpulse in a train can be varied.

FIG. 2C illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe stimulator coils or electrodes. As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the coil 341 or electrodes 340 that deliver the stimulating,blocking and/or modulating impulse 410 to the nerve. Nervestimulating/modulating device 301 or 302 may be externally poweredand/or recharged or may have its own power source 320. The parameters ofthe modulation signal 400, such as the frequency, amplitude, duty cycle,pulse width, pulse shape, etc., are preferably programmable. An externalcommunication device may modify the pulse generator programming toimprove treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes orcoils, the device disclosed in patent publication No. US2005/0216062 maybe employed. That patent publication discloses a multifunctionalelectrical stimulation (ES) system adapted to yield output signals foreffecting electromagnetic or other forms of electrical stimulation for abroad spectrum of different biological and biomedical applications,which produce an electric field pulse in order to non-invasivelystimulate nerves. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape, such as a sine wave, asquare or a saw-tooth wave, or simple or complex pulse, the parametersof which are adjustable in regard to amplitude, duration, repetitionrate and other variables. Examples of the signals that may be generatedby such a system are described in a publication by LIBOFF [A. R. LIBOFF.Signal shapes in electromagnetic therapies: a primer. pp. 17-37 in:Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov, eds.).New York: Marcel Dekker (2004)]. The signal from the selected generatorin the ES stage is fed to at least one output stage where it isprocessed to produce a high or low voltage or current output of adesired polarity whereby the output stage is capable of yielding anelectrical stimulation signal appropriate for its intended application.Also included in the system is a measuring stage which measures anddisplays the electrical stimulation signal operating on the substancebeing treated, as well as the outputs of various sensors which senseprevailing conditions prevailing in this substance, whereby the user ofthe system can manually adjust the signal, or have it automaticallyadjusted by feedback, to provide an electrical stimulation signal ofwhatever type the user wishes, who can then observe the effect of thissignal on a substance being treated.

The stimulating and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely, stimulatingand/or modulating some or all of the transmission of the selected nerve.For example, the frequency may be about 1 Hz or greater, such as betweenabout 15 Hz to about 100 Hz, preferably between about 15-50 Hz and morepreferably between about 15-35 Hz. In an exemplary embodiment, thefrequency is about 25 Hz. The modulation signal may have a pulse widthselected to influence the therapeutic result, such as about 1microseconds to about 1000 microseconds, preferably about 100-400microseconds and more preferably about 200-400 microseconds. Forexample, the electric field induced or produced by the device withintissue in the vicinity of a nerve may be about 5 to about 600 V/m,preferably less than about 100 V/m, and even more preferably less thanabout 30 V/m. The gradient of the electric field may be greater thanabout 2 V/m/mm. More generally, the stimulation device produces anelectric field in the vicinity of the nerve that is sufficient to causethe nerve to depolarize and reach a threshold for action potentialpropagation, which is about 8 V/m at 1000 Hz. The modulation signal mayhave a peak voltage amplitude selected to influence the therapeuticresult, such as about 0.2 volts or greater, such as about 0.2 volts toabout 40 volts, preferably about 1-20 volts and more preferably about2-12 volts.

An objective of the disclosed stimulators is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode or coil configuration, andnerve fiber selectivity may be achieved in part through the design ofthe stimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement others that are used to achieve selective nervestimulation, such as the use of local anesthetic, application ofpressure, inducement of ischemia, cooling, use of ultrasound, gradedincreases in stimulus intensity, exploiting the absolute refractoryperiod of axons, and the application of stimulus blocks [John E. SWETTand Charles M. Bourassa. Electrical stimulation of peripheral nerve. In:Electrical Stimulation Research Techniques, Michael M. Patterson andRaymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inU.S. Pat. No. 6,234,953, entitled Electrotherapy device using lowfrequency magnetic pulses, to THOMAS et al. and application numberUS20090299435, entitled Systems and methods for enhancing or affectingneural stimulation efficiency and/or efficacy, to GLINER et al. One mayalso vary stimulation parameters iteratively, in search of an optimalsetting [U.S. Pat. No. 7,869,885, entitled Threshold optimization fortissue stimulation therapy, to BEGNAUD et al]. However, some stimulationwaveforms, such as those described herein, are discovered by trial anderror, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they produce excessive pain. Prepulses andsimilar waveform modifications have been suggested as methods to improveselectivity of nerve stimulation waveforms, but Applicant did not findthem ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J. Struijk. Acomparative study of three techniques for diameter selective fiberactivation in the vagal nerve: anodal block, depolarizing prepulses andslowly rising pulses. J. Neural Eng. 5 (2008): 275-286; AleksandraVUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk. Different PulseShapes to Obtain Small Fiber Selective Activation by Anodal Blocking—ASimulation Study. IEEE Transactions on Biomedical Engineering 51(5,2004):698-706; Kristian HENNINGS. Selective Electrical Stimulation ofPeripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis,Center for Sensory-Motor Interaction, Aalborg University, Aalborg,Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340, entitledStimulation design for neuromodulation, to De Ridder]. However, burstsof sinusoidal pulses are a preferred stimulation waveform, as shown inFIGS. 2D and 2E. As seen there, individual sinusoidal pulses have aperiod of, and a burst consists of N such pulses. This is followed by aperiod with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period may be between about 50-1000microseconds (equivalent to about 1-20 KHz), preferably between about100-400 microseconds (equivalent to about 2.5-10 KHz), more preferablyabout 133-400 microseconds (equivalent to about 2.5-7.5 KHZ) and evenmore preferably about 200 microseconds (equivalent to about 5 KHz); thenumber of pulses per burst may be N=1-20, preferably about 2-10 and morepreferably about 5; and the whole pattern of burst followed by silentinter-burst period may have a period T comparable to about 10-100 Hz,preferably about 15-50 Hz, more preferably about 25-35 Hz and even morepreferably about 25 Hz (a much smaller value of T is shown in FIG. 2E tomake the bursts discernable). When these exemplary values are used for Tand, the waveform contains significant Fourier components at higherfrequencies (1/200 microseconds=5000/sec), as compared with thosecontained in transcutaneous nerve stimulation waveforms, as currentlypracticed.

Applicant is unaware of such a waveform having been used with vagusnerve stimulation, but a similar waveform has been used to stimulatemuscle as a means of increasing muscle strength in elite athletes.However, for the muscle strengthening application, the currents used(200 mA) may be very painful and two orders of magnitude larger thanwhat are disclosed herein. Furthermore, the signal used for musclestrengthening may be other than sinusoidal (e.g., triangular), and theparameters, N, and T may also be dissimilar from the values exemplifiedabove [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, and R. C. Lehman.Electrical stimulation of the quadriceps femoris in an elite weightlifter: a single subject experiment. Int J Sports Med 10 (1989):187-191;Alex R WARD, Nataliya Shkuratova. Russian Electrical Stimulation: TheEarly Experiments. Physical Therapy 82 (10, 2002): 1019-1030; YochevedLAUFER and Michal Elboim. Effect of Burst Frequency and Duration ofKilohertz-Frequency Alternating Currents and of Low-Frequency PulsedCurrents on Strength of Contraction, Muscle Fatigue, and PerceivedDiscomfort. Physical Therapy 88 (10, 2008):1167-1176; Alex R WARD.Electrical Stimulation Using Kilohertz-Frequency Alternating Current.Physical Therapy 89 (2, 2009):181-190; J. PETROFSKY, M. Laymon, M.Prowse, S. Gunda, and J. Batt. The transfer of current through skin andmuscle during electrical stimulation with sine, square, Russian andinterferential waveforms. Journal of Medical Engineering and Technology33 (2, 2009): 170-181; U.S. Pat. No. 4,177,819, entitled Musclestimulating apparatus, to KOFSKY et al]. Burst stimulation has also beendisclosed in connection with implantable pulse generators, but whereinthe bursting is characteristic of the neuronal firing pattern itself[U.S. Pat. No. 7,734,340 to DE RIDDER, entitled Stimulation design forneuromodulation; application US20110184486 to DE RIDDER, entitledCombination of tonic and burst stimulations to treat neurologicaldisorders]. By way of example, the electric field shown in FIGS. 2D and2E may have an E_(max) value of 17 V/m, which is sufficient to stimulatethe nerve but is significantly lower than the threshold needed tostimulate surrounding muscle.

High frequency electrical stimulation is also known in the treatment ofback pain at the spine [Patent application US20120197369, entitledSelective high frequency spinal cord modulation for inhibiting pain withreduced side effects and associated systems and methods, to ALATARIS etal.; Adrian A L KAISY, Iris Smet, and Jean-Pierre Van Buyten. Analgeiaof axial low back pain with novel spinal neuromodulation. Posterpresentation #202 at the 2011 meeting of The American Academy of PainMedicine, held in National Harbor, Md., Mar. 24-27, 2011].

Those methods involve high-frequency modulation in the range of fromabout 1.5 KHz to about 50 KHz, which is applied to the patient's spinalcord region. However, such methods are different from the presentinvention because, for example, they is invasive; they do not involve abursting waveform, as in the present invention; they necessarily involveA-delta and C nerve fibers and the pain that those fibers produce,whereas the present invention does not; they may involve a conductionblock applied at the dorsal root level, whereas the present inventionmay stimulate action potentials without blocking of such actionpotentials; and/or they involve an increased ability of high frequencymodulation to penetrate through the cerebral spinal fluid, which is notrelevant to the present invention. In fact, a likely explanation for thereduced back pain that is produced by their use of frequencies from 10to 50 KHz is that the applied electrical stimulus at those frequenciescauses permanent damage to the pain-causing nerves, whereas the presentinvention involves only reversible effects [LEE R C, Zhang D, Hannig J.Biophysical injury mechanisms in electrical shock trauma. Annu RevBiomed Eng 2 (2000):477-509].

Consider now which nerve fibers may be stimulated by the non-invasivevagus nerve stimulation. The waveform disclosed in FIG. 2 containssignificant Fourier components at high frequencies (e.g., 1/200microseconds=5000/sec), even if the waveform also has components atlower frequencies (e.g., 25/sec). Transcutaneously, A-beta, A-delta, andC fibers are typically excited at 2000 Hz, 250 Hz, and 5 Hz,respectively, i.e., the 2000 Hz stimulus is described as being specificfor measuring the response of A-beta fibers, the 250 Hz for A-deltafibers, and the 5 Hz for type C fibers [George D. BAQUIS et al.TECHNOLOGY REVIEW: THE NEUROMETER CURRENT PERCEPTION THRESHOLD (CPT).Muscle Nerve 22(Supplement 8, 1999): S247-S259]. Therefore, the highfrequency component of the noninvasive stimulation waveform willpreferentially stimulate the A-alpha and A-beta fibers, and the C fiberswill be largely unstimulated.

However, the threshold for activation of fiber types also depends on theamplitude of the stimulation, and for a given stimulation frequency, thethreshold increases as the fiber size decreases. The threshold forgenerating an action potential in nerve fibers that are impaled withelectrodes is traditionally described by Lapicque or Weiss equations,which describe how together the width and amplitude of stimulus pulsesdetermine the threshold, along with parameters that characterize thefiber (the chronaxy and rheobase). For nerve fibers that are stimulatedby electric fields that are applied externally to the fiber, as is thecase here, characterizing the threshold as a function of pulse amplitudeand frequency is more complicated, which ordinarily involves thenumerical solution of model differential equations or a case-by-caseexperimental evaluation [David BOINAGROV, Jim Loudin and DanielPalanker. Strength-Duration Relationship for Extracellular NeuralStimulation: Numerical and Analytical Models. J Neurophysiol 104(2010):2236-2248].

For example, REILLY describes a model (the spatially extended nonlinearnodal model or SENN model) that may be used to calculate minimumstimulus thresholds for nerve fibers having different diameters [J.Patrick REILLY. Electrical models for neural excitation studies. JohnsHopkins APL Technical Digest 9(1, 1988): 44-59]. According to REILLY'sanalysis, the minimum threshold for excitation of myelinated A fibers is6.2 V/m for a 20 μm diameter fiber, 12.3 V/m for a 10 μm fiber, and 24.6V/m for a 5 μm diameter fiber, assuming a pulse width that is within thecontemplated range of the present invention (1 ms). It is understoodthat these thresholds may differ slightly from those produced by thewaveform of the present invention as illustrated by REILLY's figures,for example, because the present invention prefers to use sinusoidalrather than square pulses. Thresholds for B and C fibers arerespectively 2 to 3 and 10 to 100 times greater than those for A fibers[Mark A. CASTORO, Paul B. Yoo, Juan G. Hincapie, Jason J. Hamann,Stephen B. Ruble, Patrick D. Wolf, Warren M. Grill. Excitationproperties of the right cervical vagus nerve in adult dogs. ExperimentalNeurology 227 (2011): 62-68]. If we assume an average A fiber thresholdof 15 V/m, then B fibers would have thresholds of 30 to 45 V/m and Cfibers would have thresholds of 150 to 1500 V/m. The present inventionproduces electric fields at the vagus nerve in the range of about 6 toabout 100 V/m, which is therefore generally sufficient to excite allmyelinated A and B fibers, but not the unmyelinated C fibers. Incontrast, invasive vagus nerve stimulators that have been used for thetreatment of epilepsy have been reported to excite C fibers in somepatients [EVANS MS, Verma-Ahuja S, Naritoku D K, Espinosa J A.Intraoperative human vagus nerve compound action potentials. Acta NeurolScand 110 (2004): 232-238].

It is understood that although devices of the present invention maystimulate A and B nerve fibers, in practice they may also be used so asnot to stimulate the largest A fibers (A-delta) and B fibers. Inparticular, if the stimulator amplitude has been increased to the pointat which unwanted side effects begin to occur, the operator of thedevice may simply reduce the amplitude to avoid those effects. Forexample, vagal efferent fibers responsible for bronchoconstriction havebeen observed to have conduction velocities in the range of those of Bfibers. In those experiments, bronchoconstriction was only produced whenB fibers were activated, and became maximal before C fibers had beenrecruited [R. M. McALLEN and K. M. Spyer. Two types of vagalpreganglionic motoneurones projecting to the heart and lungs. J.Physiol. 282 (1978): 353-364]. Because proper stimulation with thedisclosed devices does not result in the side-effect ofbronchoconstriction, evidently the bronchoconstrictive B-fibers arepossibly not being activated when the amplitude is properly set. Also,the absence of bradycardia or prolongation of PR interval suggests thatcardiac efferent B-fibers are not stimulated. Similarly, A-deltaafferents may behave physiologically like C fibers. Because stimulationwith the disclosed devices does not produce nociceptive effects thatwould be produced by jugular A-delta fibers or C fibers, evidently theA-delta fibers may not be stimulated when the amplitude is properly set.

To summarize the foregoing discussion, the delivery of an impulse ofenergy sufficient to stimulate and/or modulate transmission of signalsof vagus nerve fibers will result in the inhibition of excitatoryneurotramsmitters and to a more normal activity within higher centers ofthe brain, many of which are components of resting state networks. Themost likely mechanisms do not involve the stimulation of C fibers; andthe stimulation of afferent nerve fibers activates neural pathwayscauses the release of norepinephrine, and/or serotonin and/or GABA.

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient (see FIG. 8). In fact, theabsence of significant fluctuation in naturally occurring physiologicalsignals from a patient is ordinarily considered to be an indication thatthe patient is in ill health. This is because a pathological controlsystem that regulates the patient's physiological variables may havebecome trapped around only one of two or more possible steady states andis therefore unable to respond normally to external and internalstresses. Accordingly, even if feedback is not used to generate themodulation signal 400, it may be useful to artificially modulate thesignal in an aperiodic fashion, in such a way as to simulatefluctuations that would occur naturally in a healthy individual. Thus,the noisy modulation of the stimulation signal may cause a pathologicalphysiological control system to be reset or undergo a non-linear phasetransition, through a mechanism known as stochastic resonance [B. SUKI,A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade,E. P. Ingenito, S. Zapperi, H. E. Stanley, Life-support system benefitsfrom noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham,Linda G Girling and John F Brewster. Fractal ventilation enhancesrespiratory sinus arrhythmia. Respiratory Research 2005, 6:41, pp. 1-9].

So, in one embodiment of the present invention, the modulation signal400, with or without feedback, will stimulate the selected nerve fibersin such a way that one or more of the stimulation parameters (power,frequency, and others mentioned herein) are varied by sampling astatistical distribution having a mean corresponding to a selected, orto a most recent running-averaged value of the parameter, and thensetting the value of the parameter to the randomly sampled value. Thesampled statistical distributions will comprise Gaussian and 1/f,obtained from recorded naturally occurring random time series or bycalculated formula. Parameter values will be so changed periodically, orat time intervals that are themselves selected randomly by samplinganother statistical distribution, having a selected mean and coefficientof variation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In another embodiment, devices in accordance with the present inventionare provided in a “pacemaker” type form, in which electrical impulses410 are generated to a selected region of the nerve by a stimulatordevice on an intermittent basis, to create in the patient a lowerreactivity of the nerve.

Preferred Embodiments of the Magnetic Stimulator

A preferred embodiment of magnetic stimulator coil 341 comprises atoroidal winding around a core consisting of high-permeability material(e.g., Supermendur), embedded in an electrically conducting medium.Toroidal coils with high permeability cores have been theoreticallyshown to greatly reduce the currents required for transcranial (TMS) andother forms of magnetic stimulation, but only if the toroids areembedded in a conducting medium and placed against tissue with no airinterface [Rafael CARBUNARU and Dominique M. Durand. Toroidal coilmodels for transcutaneous magnetic stimulation of nerves. IEEETransactions on Biomedical Engineering 48 (4, 2001): 434-441; RafaelCarbunaru FAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999, (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)].

Although Carbunaru and Durand demonstrated that it is possible toelectrically stimulate a patient transcutaneously with such a device,they made no attempt to develop the device in such a way as to generallyshape the electric field that is to stimulate the nerve. In particular,the electric fields that may be produced by their device are limited tothose that are radially symmetric at any given depth of stimulation intothe patient (i.e, two variables, z and rho, are used to specify locationof the field, not x, y, and z). This is a significant limitation, and itresults in a deficiency that was noted in FIG. 6 of their publication:“at large depths of stimulation, the threshold current [in the device'scoil] for long axons is larger than the saturation current of the coil.Stimulation of those axons is only possible at low threshold points suchas bending sites or tissue conductivity inhomogeneities”. Thus, fortheir device, varying the parameters that they considered, in order toincrease the electric field or its gradient in the vicinity of a nerve,may come at the expense of limiting the field's physiologicaleffectiveness, such that the spatial extent of the field of stimulationmay be insufficient to modulate the target nerve's function. Yet, suchlong axons are precisely what we may wish to stimulate in therapeuticinterventions, such as the ones disclosed herein.

Accordingly, it is an objective of the present invention to shape anelongated electric field of effect that can be oriented parallel to sucha long nerve. The term “shape an electric field” as used herein means tocreate an electric field or its gradient that is generally not radiallysymmetric at a given depth of stimulation in the patient, especially afield that is characterized as being elongated or finger-like, andespecially also a field in which the magnitude of the field in somedirection may exhibit more than one spatial maximum (i.e. may be bimodalor multimodal) such that the tissue between the maxima may contain anarea across which induced current flow is restricted. Shaping of theelectric field refers both to the circumscribing of regions within whichthere is a significant electric field and to configuring the directionsof the electric field within those regions. The shaping of the electricfield is described in terms of the corresponding field equations incommonly assigned application US20110125203 (application Ser. No.12/964,050), entitled Magnetic stimulation devices and methods oftherapy, to SIMON et al., which is hereby incorporated by reference.

Thus, the present invention differs from the device disclosed byCARBUNARU and Durand by deliberately shaping an electric field that isused to transcutaneously stimulate the patient. Whereas the toroid inthe CARBUNARU and Durand publication was immersed in a homogeneousconducting half-space, this is not necessarily the case for ourinvention. Although our invention will generally have some continuouslyconducting path between the device's coil and the patient's skin, theconducting medium need not totally immerse the coil, and there may beinsulating voids within the conducting medium. For example, if thedevice contains two toroids, conducting material may connect each of thetoroids individually to the patient's skin, but there may be aninsulating gap (from air or some other insulator) between the surfacesat which conducting material connected to the individual toroids contactthe patient. Furthermore, the area of the conducting material thatcontacts the skin may be made variable, by using an aperture adjustingmechanism such as an iris diaphragm. As another example, if the coil iswound around core material that is laminated, with the core in contactwith the device's electrically conducting material, then the laminationmay be extended into the conducting material in such a way as to directthe induced electrical current between the laminations and towards thesurface of the patient's skin. As another example, the conductingmaterial may pass through apertures in an insulated mesh beforecontacting the patient's skin, creating thereby an array of electricfield maxima.

In the dissertation cited above, Carbunaru—FAIERSTEIN made no attempt touse conducting material other than agar in a KCI solution, and he madeno attempt to devise a device that could be conveniently and safelyapplied to a patient's skin, at an arbitrary angle without theconducting material spilling out of its container. It is therefore anobjective of the present invention to disclose conducting material thatcan be used not only to adapt the conductivity of the conductingmaterial and select boundary conditions, thereby shaping the electricfields and currents as described above, but also to create devices thatcan be applied practically to any surface of the body. The volume of thecontainer containing electrically conducting medium is labeled in FIG.2A as 351. Use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 percentto about 0.1 percent of the current conventionally applied to a magneticstimulation coil. This allows for minimal heating of the coil(s) anddeeper tissue stimulation. However, application of the conducting mediumto the surface of the patient is difficult to perform in practicebecause the tissue contours (head, arms, legs, neck, etc.) are notplanar. To solve this problem, in the preferred embodiment of thepresent invention, the toroidal coil is embedded in a structure which isfilled with a conducting medium having approximately the sameconductivity as muscle tissue, as now described.

In one embodiment of the invention, the container contains holes so thatthe conducting material (e.g., a conducting gel) can make physicalcontact with the patient's skin through the holes. For example, theconducting medium 351 may comprise a chamber surrounding the coil,filled with a conductive gel that has the approximate viscosity andmechanical consistency of gel deodorant (e.g., Right Guard Clear Gelfrom Dial Corporation, 15501 N. Dial Boulevard, Scottsdale Ariz. 85260,one composition of which comprises aluminum chlorohydrate, sorbitol,propylene glycol, polydimethylsiloxanes Silicon oil, cyclomethicone,ethanol/SD Alcohol 40, dimethicone copolyol, aluminum zirconiumtetrachlorohydrex gly, and water). The gel, which is less viscous thanconventional electrode gel, is maintained in the chamber with a mesh ofopenings at the end where the device is to contact the patient's skin.The gel does not leak out, and it can be dispensed with a simple screwdriven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue. A device such as that disclosed in U.S. Pat. No.7,591,776, entitled Magnetic stimulators and stimulating coils, toPHILLIPS et al. may conform the coil itself to the contours of the body,but in the preferred embodiment, such a curved coil is also enclosed bya container that is filled with a conducting medium that deforms to becontiguous with the skin.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient and stimulatorcoil. Use of agar in a 4M KCI solution as a conducting medium wasmentioned in the above-cited dissertation: Rafael Carbunaru FAIERSTEIN,Coil Designs for Localized and Efficient Magnetic Stimulation of theNervous System. Ph.D. Dissertation, Department of BiomedicalEngineering, Case Western Reserve, May, 1999, page 117 (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.). However, thatpublication makes no mention or suggestion of placing the agar in aconducting elastomeric balloon, or other deformable container so as toallow the conducting medium to conform to the generally non-planarcontours of a patient's skin having an arbitrary orientation. In fact,that publication describes the coil as being submerged in a containerfilled with an electrically conducting solution. If the coil andcontainer were placed on a body surface that was oriented in thevertical direction, then the conducting solution would spill out, makingit impossible to stimulate the body surface in that orientation. Incontrast, the present invention is able to stimulate body surfaceshaving arbitrary orientation.

That dissertation also makes no mention of a dispensing method wherebythe agar would be made contiguous with the patient's skin. A layer ofelectrolytic gel is said to have been applied between the skin and coil,but the configuration was not described clearly in the publication. Inparticular, no mention is made of the electrolytic gel being in contactwith the agar.

Rather than using agar as the conducting medium, the coil can instead beembedded in a conducting solution such as 1-10% NaCl, contacting anelectrically conducting interface to the human tissue. Such an interfaceis used as it allows current to flow from the coil into the tissue andsupports the medium-surrounded toroid so that it can be completelysealed. Thus, the interface is material, interposed between theconducting medium and patient's skin, that allows the conducting medium(e.g., saline solution) to slowly leak through it, allowing current toflow to the skin. Several interfaces are disclosed as follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J. Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13 pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the toroid and the solution it isembedded in from the tissue, yet allow current to pass.

The preferred embodiment of the magnetic stimulator coil 341 in FIG. 2Areduces the volume of conducting material that must surround a toroidalcoil, by using two toroids, side-by-side, and passing electrical currentthrough the two toroidal coils in opposite directions. In thisconfiguration, the induced current will flow from the lumen of onetoroid, through the tissue and back through the lumen of the other,completing the circuit within the toroids' conducting medium. Thus,minimal space for the conducting medium is required around the outsideof the toroids at positions near from the gap between the pair of coils.An additional advantage of using two toroids in this configuration isthat this design will greatly increase the magnitude of the electricfield gradient between them, which is crucial for exciting long,straight axons such as the vagus nerve and certain other peripheralnerves.

This preferred embodiment of the magnetic stimulation device is shown inFIG. 3. FIGS. 3A and 3B respectively provide top and bottom views of theouter surface of the toroidal magnetic stimulator 30. FIGS. 3C and 3Drespectively provide top and bottom views of the toroidal magneticstimulator 30, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 3A-3D all show a mesh 31 with openings that permit a conductinggel to pass from the inside of the stimulator to the surface of thepatient's skin at the location of nerve or tissue stimulation. Thus, themesh with openings 31 is the part of the stimulator that is applied tothe skin of the patient.

FIGS. 3B-3D show openings at the opposite end of the stimulator 30. Oneof the openings is an electronics port 32 through which wires pass fromthe stimulator coil(s) to the impulse generator (310 in FIG. 2A). Thesecond opening is a conducting gel port 33 through which conducting gelmay be introduced into the stimulator 30 and through which ascrew-driven piston arm may be introduced to dispense conducting gelthrough the mesh 31. The gel itself will be contained withincylindrical-shaped but interconnected conducting medium chambers 34 thatare shown in FIGS. 3C and 3D. The depth of the conducting mediumchambers 34, which is approximately the height of the long axis of thestimulator, affects the magnitude of the electric fields and currentsthat are induced by the device [Rafael CARBUNARU and Dominique M.Durand. Toroidal coil models for transcutaneous magnetic stimulation ofnerves. IEEE Transactions on Biomedical Engineering. 48 (4, 2001):434-441].

FIGS. 3C and 3D also show the coils of wire 35 that are wound aroundtoroidal cores 36, consisting of high-permeability material (e.g.,Supermendur). Lead wires (not shown) for the coils 35 pass from thestimulator coil(s) to the impulse generator (310 in FIG. 1) via theelectronics port 32. Different circuit configurations are contemplated.If separate lead wires for each of the coils 35 connect to the impulsegenerator (i.e., parallel connection), and if the pair of coils arewound with the same handedness around the cores, then the design is forcurrent to pass in opposite directions through the two coils. On theother hand, if the coils are wound with opposite handedness around thecores, then the lead wires for the coils may be connected in series tothe impulse generator, or if they are connected to the impulse generatorin parallel, then the design is for current to pass in the samedirection through both coils.

As seen in FIGS. 3C and 3D, the coils 35 and cores 36 around which theyare wound are mounted as close as practical to the corresponding mesh 31with openings through which conducting gel passes to the surface of thepatient's skin. As seen in FIG. 3D, each coil and the core around whichit is wound is mounted in its own housing 37, the function of which isto provide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance.

Signal generators for magnetic stimulators have been described forcommercial systems [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006], as well as for customdesigns for a control unit 330, impulse generator 310 and power source320 [Eric BASHAM, Zhi Yang, Natalia Tchemodanov, and Wentai Liu.Magnetic Stimulation of Neural Tissue: Techniques and System Design. pp293-352, In: Implantable Neural Prostheses 1, Devices and Applications,D. Zhou and E. Greenbaum, eds., New York: Springer (2009); U.S. Pat. No.7,744,523, entitled Drive circuit for magnetic stimulation, to CharlesM. Epstein; U.S. Pat. No. 5,718,662, entitled Apparatus for the magneticstimulation of cells or tissue, to Reza Jalinous; U.S. Pat. No.5,766,124, entitled Magnetic stimulator for neuro-muscular tissue, toPolson]. Conventional magnetic nerve stimulators use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil, and which therebyproduces a magnetic pulse. Typically, a transformer charges a capacitorin the impulse generator 310, which also contains circuit elements thatlimit the effect of undesirable electrical transients. Charging of thecapacitor is under the control of a control unit 330, which acceptsinformation such as the capacitor voltage, power and other parametersset by the user, as well as from various safety interlocks within theequipment that ensure proper operation, and the capacitor is thendischarged through the coil via an electronic switch (e.g., a controlledrectifier) when the user wishes to apply the stimulus.

Greater flexibility is obtained by adding to the impulse generator abank of capacitors that can be discharged at different times. Thus,higher impulse rates may be achieved by discharging capacitors in thebank sequentially, such that recharging of capacitors is performed whileother capacitors in the bank are being discharged. Furthermore, bydischarging some capacitors while the discharge of other capacitors isin progress, by discharging the capacitors through resistors havingvariable resistance, and by controlling the polarity of the discharge,the control unit may synthesize pulse shapes that approximate anarbitrary function.

The design and methods of use of impulse generators, control units, andstimulator coils for magnetic stimulators are informed by the designsand methods of use of impulse generators, control units, and electrodes(with leads) for comparable completely electrical nerve stimulators, butdesign and methods of use of the magnetic stimulators must take intoaccount many special considerations, making it generally notstraightforward to transfer knowledge of completely electricalstimulation methods to magnetic stimulation methods. Such considerationsinclude determining the anatomical location of the stimulation anddetermining the appropriate pulse configuration [OLNEY R K, So Y T,Goodin D S, Aminoff M J. A comparison of magnetic and electricstimulation of peripheral nerves. Muscle Nerve 1990:13:957-963; J.NILSSON, M. Panizza, B. J. Roth et al. Determining the site ofstimulation during magnetic stimulation of the peripheral nerve,Electroencephalographs and clinical neurophysiology 85 (1992): 253-264;Nafia A L-MUTAWALY, Hubert de Bruin, and Gary Hasey. The effects ofpulse configuration on magnetic stimulation. Journal of ClinicalNeurophysiology 20(5):361-370, 2003].

Furthermore, a potential practical disadvantage of using magneticstimulator coils is that they may overheat when used over an extendedperiod of time. Use of the above-mentioned toroidal coil and containerof electrically conducting medium addresses this potential disadvantage.However, because of the poor coupling between the stimulating coils andthe nerve tissue, large currents are nevertheless required to reachthreshold electric fields. At high repetition rates, these currents canheat the coils to unacceptable levels in seconds to minutes depending onthe power levels and pulse durations and rates. Two approaches toovercome heating are to cool the coils with flowing water or air or toincrease the magnetic fields using ferrite cores (thus allowing smallercurrents). For some applications where relatively long treatment timesat high stimulation frequencies may be required, neither of these twoapproaches are adequate. Water-cooled coils overheat in a few minutes.Ferrite core coils heat more slowly due to the lower currents and heatcapacity of the ferrite core, but also cool off more slowly and do notallow for water-cooling since the ferrite core takes up the volume wherethe cooling water would flow.

A solution to this problem is to use a fluid which containsferromagnetic particles in suspension like a ferrofluid, ormagnetorheological fluid as the cooling material. Ferrofluids arecolloidal mixtures composed of nanoscale ferromagnetic, orferrimagnetic, particles suspended in a carrier fluid, usually anorganic solvent or water. The ferromagnetic nanoparticles are coatedwith a surfactant to prevent their agglomeration (due to van der Waalsforces and magnetic forces). Ferrofluids have a higher heat capacitythan water and will thus act as better coolants. In addition, the fluidwill act as a ferrite core to increase the magnetic field strength.Also, since ferrofluids are paramagnetic, they obey Curie's law, andthus become less magnetic at higher temperatures. The strong magneticfield created by the magnetic stimulator coil will attract coldferrofluid more than hot ferrofluid thus forcing the heated ferrofluidaway from the coil. Thus, cooling may not require pumping of theferrofluid through the coil, but only a simple convective system forcooling. This is an efficient cooling method which may require noadditional energy input [U.S. Pat. No. 7,396,326 and publishedapplications US2008/0114199, US2008/0177128, and US2008/0224808, allentitled Ferrofluid cooling and acoustical noise reduction in magneticstimulators, respectively to Ghiron et al., Riehl et al., Riehl et al.and Ghiron et al.].

Magnetorheological fluids are similar to ferrofluids but contain largermagnetic particles which have multiple magnetic domains rather than thesingle domains of ferrofluids. [U.S. Pat. No. 6,743,371, Magnetosensitive fluid composition and a process for preparation thereof, toJohn et al.]. They can have a significantly higher magnetic permeabilitythan ferrofluids and a higher volume fraction of iron to carrier.Combinations of magnetorheological and ferrofluids may also be used [M TLOPEZ-LOPEZ, P Kuzhir, S Lacis, G Bossis, F Gonzalez-Caballero and J D GDuran. Magnetorheology for suspensions of solid particles dispersed inferrofluids. J. Phys.: Condens. Matter 18 (2006) S2803-S2813; LadislauVEKAS. Ferrofluids and Magnetorheological Fluids. Advances in Scienceand Technology Vol. 54 (2008) pp 127-136.].

Commercially available magnetic stimulators include circular, parabolic,figure-of-eight (butterfly), and custom designs that are availablecommercially [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006]. Additional embodimentsof the magnetic stimulator coil 341 have been described [U.S. Pat. No.6,179,770, entitled Coil assemblies for magnetic stimulators, to StephenMould; Kent DAVEY. Magnetic Stimulation Coil and Circuit Design. IEEETransactions on Biomedical Engineering, Vol. 47 (No. 11, November 2000):1493-1499]. Many of the problems that are associated with suchconventional magnetic stimulators, e.g., the complexity of theimpulse-generator circuitry and the problem with overheating, arelargely avoided by the toroidal design shown in FIG. 3.

Thus, use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 percentto about 0.1 percent of the current conventionally applied to a magneticstimulation coil. Therefore, with the present invention, it is possibleto generate waveforms shown in FIG. 2 with relatively simple, low-powercircuits that are powered by batteries. The circuits may be enclosedwithin a box 38 as shown in FIG. 3E, or the circuits may be attached tothe stimulator itself (FIG. 3A-3D) to be used as a hand-held device. Ineither case, control over the unit may be made using only an on/offswitch and power knob. The only other component that may be needed mightbe a cover 39 to keep the conducting fluid from leaking or drying outbetween uses. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to 100 volts. The currentis passed through the coils in bursts of pulses, as described inconnection with FIGS. 2D and 2E, shaping an elongated electrical fieldof effect.

Preferred Embodiments of the Electrode-Based Stimulator

In another embodiment of the invention, electrodes applied to thesurface of the neck, or to some other surface of the body, are used tonon-invasively deliver electrical energy to a nerve, instead ofdelivering the energy to the nerve via a magnetic coil. The vagus nervehas been stimulated previously non-invasively using electrodes appliedvia leads to the surface of the skin. It has also been stimulatednon-electrically through the use of mechanical vibration [HUSTON J M,Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M et al(2007). Transcutaneous vagus nerve stimulation reduces serum highmobility group box 1 levels and improves survival in murine sepsis. CritCare Med 35: 2762-2768; GEORGE MS, Aston-Jones G. Noninvasive techniquesfor probing neurocircuitry and treating illness: vagus nerve stimulation(VNS), transcranial magnetic stimulation (TMS) and transcranial directcurrent stimulation (tDCS). Neuropsychopharmacology 35(1,2010):301-316]. However, no such reported uses of noninvasive vagusnerve stimulation were directed to the treatment of stroke or transientischemic attack patients. U.S. Pat. No. 7,340,299, entitled Methods ofindirectly stimulating the vagus nerve to achieve controlled asystole,to John D. PUSKAS, discloses the stimulation of the vagus nerve usingelectrodes placed on the neck of the patient, but that patent isunrelated to the treatment of stroke or transient ischemic attacks.Non-invasive electrical stimulation of the vagus nerve has also beendescribed in Japanese patent application JP2009233024A with a filingdate of Mar. 26, 2008, entitled Vagus Nerve Stimulation System, to FukuiYOSHIHOTO, in which a body surface electrode is applied to the neck tostimulate the vagus nerve electrically. However, that applicationpertains to the control of heart rate and is unrelated to the treatmentof stroke or transient ischemic attacks. In patent publicationUS20080208266, entitled System and method for treating nausea andvomiting by vagus nerve stimulation, to LESSER et al., electrodes areused to stimulate the vagus nerve in the neck to reduce nausea andvomiting, but this too is unrelated to the treatment of stroke ortransient ischemic attacks.

Patent application US2010/0057154, entitled Device and method for thetransdermal stimulation of a nerve of the human body, to DIETRICH etal., discloses a non-invasive transcutaneous/transdermal method forstimulating the vagus nerve, at an anatomical location where the vagusnerve has paths in the skin of the external auditory canal. Theirnon-invasive method involves performing electrical stimulation at thatlocation, using surface stimulators that are similar to those used forperipheral nerve and muscle stimulation for treatment of pain(transdermal electrical nerve stimulation), muscle training (electricalmuscle stimulation) and electroacupuncture of defined meridian points.The method used in that application is similar to the ones used in U.S.Pat. No. 4,319,584, entitled Electrical pulse acupressure system, toMcCALL, for electroacupuncture; U.S. Pat. No. 5,514,175 entitledAuricular electrical stimulator, to KIM et al., for the treatment ofpain; and U.S. Pat. No. 4,966,164, entitled Combined sound generatingdevice and electrical acupuncture device and method for using the same,to COLSEN et al., for combined sound/electroacupuncture. A relatedapplication is US2006/0122675, entitled Stimulator for auricular branchof vagus nerve, to LIBBUS et al. Similarly, U.S. Pat. No. 7,386,347,entitled Electric stimilator for alpha-wave derivation, to CHUNG et al.,described electrical stimulation of the vagus nerve at the ear. Patentapplication US2008/0288016, entitled Systems and Methods for StimulatingNeural Targets, to AMURTHUR et al., also discloses electricalstimulation of the vagus nerve at the ear. U.S. Pat. No. 4,865,048,entitled Method and apparatus for drug free neurostimulation, toECKERSON, teaches electrical stimulation of a branch of the vagus nervebehind the ear on the mastoid processes, in order to treat symptoms ofdrug withdrawal. KRAUS et al described similar methods of stimulation atthe ear [KRAUS T, Hosl K, Kiess O, Schanze A, Kornhuber J, Forster C(2007). BOLD fMRI deactivation of limbic and temporal brain structuresand mood enhancing effect by transcutaneous vagus nerve stimulation. JNeural Transm 114: 1485-1493]. However, none of the disclosures in thesepatents or patent applications for electrical stimulation of the vagusnerve at the ear are used to treat stroke or transient ischemic attacks.

Embodiments of the present invention may differ with regard to thenumber of electrodes that are used, the distance between electrodes, andwhether disk or ring electrodes are used. In preferred embodiments ofthe method, one selects the electrode configuration for individualpatients, in such a way as to optimally focus electric fields andcurrents onto the selected nerve, without generating excessive currentson the surface of the skin. This tradeoff between focality and surfacecurrents is described by DATTA et al. [Abhishek DATTA, Maged Elwassif,Fortunato Battaglia and Marom Bikson. Transcranial current stimulationfocality using disc and ring electrode configurations: FEM analysis. J.Neural Eng. 5 (2008): 163-174]. Although DATTA et al. are addressing theselection of electrode configuration specifically for transcranialcurrent stimulation, the principles that they describe are applicable toperipheral nerves as well [RATTAY F. Analysis of models forextracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36 (1989):676-682].

Considering that the nerve stimulating device 301 in FIG. 2A and thenerve stimulating device 302 in FIG. 2B both control the shape ofelectrical impulses, their functions are analogous, except that onestimulates nerves via a pulse of a magnetic field, and the otherstimulates nerves via an electrical pulse applied through surfaceelectrodes. Accordingly, general features recited for the nervestimulating device 301 apply as well to the latter stimulating device302 and will not be repeated here. The preferred parameters for eachnerve stimulating device are those that produce the desired therapeuticeffects.

A preferred embodiment of an electrode-based stimulator is shown in FIG.4A. A cross-sectional view of the stimulator along its long axis isshown in FIG. 4B. As shown, the stimulator (730) comprises two heads(731) and a body (732) that joins them. Each head (731) contains astimulating electrode. The body of the stimulator (732) contains theelectronic components and battery (not shown) that are used to generatethe signals that drive the electrodes, which are located behind theinsulating board (733) that is shown in FIG. 4B. However, in otherembodiments of the invention, the electronic components that generatethe signals that are applied to the electrodes may be separate, butconnected to the electrode head (731) using wires. Furthermore, otherembodiments of the invention may contain a single such head or ore thantwo heads.

Heads of the stimulator (731) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes or collars, or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (734) that also serves as an on/off switch. Alight (735) is illuminated when power is being supplied to thestimulator. An optional cap may be provided to cover each of thestimulator heads (731), to protect the device when not in use, to avoidaccidental stimulation, and to prevent material within the head fromleaking or drying. Thus, in this embodiment of the invention, mechanicaland electronic components of the stimulator (impulse generator, controlunit, and power source) are compact, portable, and simple to operate.

Details of one embodiment of the stimulator head are shown in FIGS. 4Cand 4D. The electrode head may be assembled from a disc withoutfenestration (743), or alternatively from a snap-on cap that serves as atambour for a dielectric or conducting membrane, or alternatively thehead may have a solid fenestrated head-cup. The electrode may also be ascrew (745). The preferred embodiment of the disc (743) is a solid,ordinarily uniformly conducting disc (e.g., metal such as stainlesssteel), which is possibly flexible in some embodiments. An alternateembodiment of the disc is a non-conducting (e.g., plastic) aperturescreen that permits electrical current to pass through its apertures,e.g., through an array of apertures (fenestration). The electrode (745,also 340 in FIG. 2B) seen in each stimulator head may have the shape ofa screw that is flattened on its tip. Pointing of the tip would make theelectrode more of a point source, such that the equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditionsthat determine the electric field. Completed assembly of the stimulatorhead is shown in FIG. 4D, which also shows how the head is attached tothe body of the stimulator (747).

If a membrane is used, it ordinarily serves as the interface shown as351 in FIG. 2B. For example, the membrane may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment, apertures of thedisc may be open, or they may be plugged with conducting material, forexample, KM10T hydrogel from Katecho Inc., 4020 Gannett Ave., Des MoinesIowa 50321. If the apertures are so-plugged, and the membrane is made ofconducting material, the membrane becomes optional, and the plug servesas the interface 351 shown in FIG. 2B.

The head-cup (744) is filled with conducting material (350 in FIG. 2B),for example, SIGNAGEL Electrode Gel from Parker Laboratories, Inc., 286Eldridge Rd., Fairfield N.J. 07004. The head-cup (744) and body of thestimulator are made of a non-conducting material, such as acrylonitrilebutadiene styrene. The depth of the head-cup from its top surface to theelectrode may be between one and six centimeters. The head-cup may havea different curvature than what is shown in FIG. 4, or it may be tubularor conical or have some other inner surface geometry that will affectthe Neumann boundary conditions that determine the electric fieldstrength.

If an outer membrane is used and is made of conducting materials, andthe disc (743) in FIG. 4C is made of solid conducting materials such asstainless steel, then the membrane becomes optional, in which case thedisc may serve as the interface 351 shown in FIG. 2B. Thus, anembodiment without the membrane is shown in FIGS. 4C and 4D. Thisversion of the device comprises a solid (but possibly flexible in someembodiments) conducting disc that cannot absorb fluid, thenon-conducting stimulator head (744) into or onto which the disc isplaced, and the electrode (745), which is also a screw. It is understoodthat the disc (743) may have an anisotropic material or electricalstructure, for example, wherein a disc of stainless steel has a grain,such that the grain of the disc should be rotated about its location onthe stimulator head, in order to achieve optimal electrical stimulationof the patient. As seen in FIG. 4D, these items are assembled to becomea sealed stimulator head that is attached to the body of the stimulator(747). The disc (743) may screw into the stimulator head (744), it maybe attached to the head with adhesive, or it may be attached by othermethods that are known in the art. The chamber of the stimulatorhead-cup is filled with a conducting gel, fluid, or paste, and becausethe disc (743) and electrode (745) are tightly sealed against thestimulator head-cup (744), the conducting material within the stimulatorhead cannot leak out. In addition, this feature allows the user toeasily clean the outer surface of the device (e.g., with isopropylalcohol or similar disinfectant), avoiding potential contaminationduring subsequent uses of the device.

In some embodiments, the interface comprises a fluid permeable materialthat allows for passage of current through the permeable portions of thematerial. In these embodiments, a conductive medium (such as a gel) ispreferably situated between the electrode(s) and the permeableinterface. The conductive medium provides a conductive pathway forelectrons to pass through the permeable interface to the outer surfaceof the interface and to the patient's skin.

In other embodiments of the present invention, the interface (351 inFIG. 2B) is made from a very thin material with a high dielectricconstant, such as material used to make capacitors. For example, it maybe Mylar having a submicron thickness (preferably in the range about 0.5to about 1.5 microns) having a dielectric constant of about 3. Becauseone side of Mylar is slick, and the other side is microscopically rough,the present invention contemplates two different configurations: one inwhich the slick side is oriented towards the patient's skin, and theother in which the rough side is so-oriented. Thus, at stimulationFourier frequencies of several kilohertz or greater, the dielectricinterface will capacitively couple the signal through itself, because itwill have an impedance comparable to that of the skin. Thus, thedielectric interface will isolate the stimulator's electrode from thetissue, yet allow current to pass. In one embodiment of the presentinvention, non-invasive electrical stimulation of a nerve isaccomplished essentially substantially capacitively, which reduces theamount of ohmic stimulation, thereby reducing the sensation the patientfeels on the tissue surface. This would correspond to a situation, forexample, in which at least 30%, preferably at least 50%, of the energystimulating the nerve comes from capacitive coupling through thestimulator interface, rather than from ohmic coupling. In other words, asubstantial portion (e.g., 50%) of the voltage drop is across thedielectric interface, while the remaining portion is through the tissue.

In certain exemplary embodiments, the interface and/or its underlyingmechanical support comprise materials that will also provide asubstantial or complete seal of the interior of the device. Thisinhibits any leakage of conducting material, such as gel, from theinterior of the device and also inhibits any fluids from entering thedevice. In addition, this feature allows the user to easily clean thesurface of the dielectric material (e.g., with isopropyl alcohol orsimilar disinfectant), avoiding potential contamination duringsubsequent uses of the device. One such material is a thin sheet ofMylar, supported by a stainless steel disc, as described above.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to about 5 microns (preferably about 1 micron) with adielectric; constant of about 3. For a piezoelectric material likebarium titanate or PZT (lead zirconate titanate), the thickness could beabout 100-400 microns (preferably about 200 microns or 0.2 mm) becausethe dielectric constant is >1000.

One of the novelties of the embodiment that is a non-invasive capacitivestimulator (hereinafter referred to more generally as a capacitiveelectrode) arises in that it uses a low voltage (generally less than 100volt) power source, which is made possible by the use of a suitablestimulation waveform, such as the waveform that is disclosed herein(FIG. 2). In addition, the capacitive electrode allows for the use of aninterface that provides a more adequate seal of the interior of thedevice. The capacitive electrode may be used by applying a small amountof conductive material (e.g., conductive gel as described above) to itsouter surface. In some embodiments, it may also be used by contactingdry skin, thereby avoiding the inconvenience of applying an electrodegel, paste, or other electrolytic material to the patient's skin andavoiding the problems associated with the drying of electrode pastes andgels. Such a dry electrode would be particularly suitable for use with apatient who exhibits dermatitis after the electrode gel is placed incontact with the skin [Ralph J. COSKEY. Contact dermatitis caused by ECGelectrode jelly. Arch Dermatol 113 (1977): 839-840]. The capacitiveelectrode may also be used to contact skin that has been wetted (e.g.,with tap water or a more conventional electrolyte material) to make theelectrode-skin contact (here the dielectric constant) more uniform [A LALEXELONESCU, G Barbero, F C M Freire, and R Merletti. Effect ofcomposition on the dielectric properties of hydrogels for biomedicalapplications. Physiol. Meas. 31 (2010) S169-S182].

As described below, capacitive biomedical electrodes are known in theart, but when used to stimulate a nerve noninvasively, a high voltagepower supply is currently used to perform the stimulation. Otherwise,prior use of capacitive biomedical electrodes has been limited toinvasive, implanted applications; to non-invasive applications thatinvolve monitoring or recording of a signal, but not stimulation oftissue; to non-invasive applications that involve the stimulation ofsomething other than a nerve (e.g., tumor); or as the dispersiveelectrode in electrosurgery.

Evidence of a long-felt but unsolved need, and evidence of failure ofothers to solve the problem that is solved by the this embodiment of thepresent invention (low-voltage, non-invasive capacitive stimulation of anerve), is provided by KELLER and Kuhn, who review the previoushigh-voltage capacitive stimulating electrode of GEDDES et al and writethat “Capacitive stimulation would be a preferred way of activatingmuscle nerves and fibers, when the inherent danger of high voltagebreakdowns of the dielectric material can be eliminated. Goal of futureresearch could be the development of improved and ultra-thin dielectricfoils, such that the high stimulation voltage can be lowered.” [L. A.GEDDES, M. Hinds, and K. S. Foster. Stimulation with capacitorelectrodes. Medical and Biological Engineering and Computing 25 (1987):359-360; Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade 18(2, 2008):35-45, on page 39]. It is understoodthat in the United States, according to the 2005 National ElectricalCode, high voltage is any voltage over 600 volts. U.S. Pat. No.3,077,884, entitled Electro-physiotherapy apparatus, to BARTROW et al,U.S. Pat. No. 4,144,893, entitled Neuromuscular therapy device, toHICKEY and U.S. Pat. No. 7,933,648, entitled High voltage transcutaneouselectrical stimulation device and method, to TANRISEVER, also describehigh voltage capacitive stimulation electrodes. U.S. Pat. No. 7,904,180,entitled Capacitive medical electrode, to JUOLA et al, describes acapacitive electrode that includes transcutaneous nerve stimulation asone intended application, but that patent does not describe stimulationvoltages or stimulation waveforms and frequencies that are to be usedfor the transcutaneous stimulation. U.S. Pat. No. 7,715,921, entitledElectrodes for applying an electric field in-vivo over an extendedperiod of time, to PALTI, and U.S. Pat. No. 7,805,201, entitled Treatinga tumor or the like with an electric field, to PALTI, also describecapacitive stimulation electrodes, but they are intended for thetreatment of tumors, do not disclose uses involving nerves, and teachstimulation frequencies in the range of 50 kHz to about 500 kHz.

This embodiment of the present invention uses a different method tolower the high stimulation voltage than developing ultra-thin dielectricfoils, namely, to use a suitable stimulation waveform, such as thewaveform that is disclosed herein (FIG. 2). That waveform hassignificant Fourier components at higher frequencies than waveforms usedfor transcutaneous nerve stimulation as currently practiced. Thus, oneof ordinary skill in the art would not have combined the claimedelements, because transcutaneous nerve stimulation is performed withwaveforms having significant Fourier components only at lowerfrequencies, and noninvasive capacitive nerve stimulation is performedat higher voltages. In fact, the elements in combination do not merelyperform the function that each element performs separately. Thedielectric material alone may be placed in contact with the skin inorder to perform pasteless or dry stimulation, with a more uniformcurrent density than is associated with ohmic stimulation, albeit withhigh stimulation voltages [L. A. GEDDES, M. Hinds, and K. S. Foster.Stimulation with capacitor electrodes. Medical and BiologicalEngineering and Computing 25 (1987): 359-360; Yongmin KIM, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990, 6): 585-619]. With regard to the waveform element, a waveformthat has significant Fourier components at higher frequencies thanwaveforms currently used for transcutaneous nerve stimulation may beused to selectively stimulate a deep nerve and avoid stimulating othernerves, as disclosed herein for both noncapacitive and capacitiveelectrodes. But it is the combination of the two elements (dielectricinterface and waveform) that makes it possible to stimulate a nervecapacitively without using the high stimulation voltage as is currentlypracticed.

Another embodiment of the electrode-based stimulator is shown in FIG. 5,showing a device in which electrically conducting material is dispensedfrom the device to the patient's skin. In this embodiment, the interface(351 in FIG. 2B) is the conducting material itself. FIGS. 5A and 5Brespectively provide top and bottom views of the outer surface of theelectrical stimulator 50. FIG. 5C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 2B), and thepower-level controller is attached to the control unit (330 in FIG. 2B)of the device. The power source battery and power-level controller, aswell as the impulse generator (310 in FIG. 2B) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 in FIG.2B) to the stimulator's electrodes 56. The two electrodes 56 are shownhere to be elliptical metal discs situated between the head compartment57 and rear compartment 55 of the stimulator 50. A partition 58separates each of the two head compartments 57 from one another and fromthe single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 2B) to each headcompartment 57. An optional non-conducting variable-aperture irisdiaphragm may be placed in front of each of the electrodes within thehead compartment 57, in order to vary the effective surface area of eachof the electrodes. Each partition 58 may also slide towards the head ofthe device in order to dispense conducting gel through the meshapertures 51. The position of each partition 58 therefore determines thedistance 59 between its electrode 56 and mesh openings 51, which isvariable in order to obtain the optimally uniform current densitythrough the mesh openings 51. The outside housing of the stimulator 50,as well as each head compartment 57 housing and its partition 58, aremade of electrically insulating material, such as acrylonitrilebutadiene styrene, so that the two head compartments are electricallyinsulated from one another. Although the embodiment in FIG. 5 is shownto be a non-capacitive stimulator, it is understood that it may beconverted into a capacitive stimulator by replacing the mesh openings 51with a dielectric material, such as a sheet of Mylar, or by covering themesh openings 51 with a sheet of such dielectric material.

In preferred embodiments of the electrode-based stimulator shown in FIG.2B, electrodes are made of a metal, such as stainless steel, platinum,or a platinum-iridium alloy. However, in other embodiments, theelectrodes may have many other sizes and shapes, and they may be made ofother materials [Thierry KELLER and Andreas Kuhn. Electrodes fortranscutaneous (surface) electrical stimulation. Journal of AutomaticControl, University of Belgrade, 18(2, 2008):35-45; G. M. LYONS, G. E.Leane, M. Clarke-Moloney, J.V. O'Brien, P.A. Grace. An investigation ofthe effect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1, 1994):29-35].

For example, the stimulator's conducting materials may be nonmagnetic,and the stimulator may be connected to the impulse generator by longnonmagnetic wires (345 in FIG. 2B), so that the stimulator may be usedin the vicinity of a strong magnetic field, possibly with added magneticshielding. As another example, there may be more than two electrodes;the electrodes may comprise multiple concentric rings; and theelectrodes may be disc-shaped or have a non-planar geometry. They may bemade of other metals or resistive materials such as silicon-rubberimpregnated with carbon that have different conductive properties[Stuart F. COGAN. Neural Stimulation and Recording Electrodes. Annu.Rev. Biomed. Eng. 2008. 10:275-309; Michael F. NOLAN. Conductivedifferences in electrodes used with transcutaneous electrical nervestimulation devices. Physical Therapy 71 (1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 4 and 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6, 2005):448-452; Dejan B. POPOVICand Mirjana B. Popovic. Automatic determination of the optimal shape ofa surface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 4and 5 provide a uniform surface current density, which would otherwisebe a potential advantage of electrode arrays, and which is a trait thatis not shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jorgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12, 2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21 (1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6, 2006):368-381; Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman.Imaging of Nonuniform Current Density at Microelectrodes byElectrogenerated Chemiluminescence. Anal. Chem. 71 (1999): 4944-4950].In fact, patients found the design shown in FIGS. 4 and 5 to be lesspainful in a direct comparison with a commercially availablegrid-pattern electrode [UltraStim grid-pattern electrode, AxelggardManufacturing Company, 520 Industrial Way, Fallbrook Calif., 2011]. Theembodiment of the electrode that uses capacitive coupling isparticularly suited to the generation of uniform stimulation currents[Yongmin KIM, H. Gunter Zieber, and Frank A. Yang. Uniformity of currentdensity under stimulating electrodes. Critical Reviews in BiomedicalEngineering 17(1990, 6): 585-619].

The electrode-based stimulator designs shown in FIGS. 4 and 5 situatethe electrode remotely from the surface of the skin within a chamber,with conducting material placed in the chamber between the skin andelectrode. Such a chamber design had been used prior to the availabilityof flexible, flat, disposable electrodes [U.S. Pat. No. 3,659,614,entitled Adjustable headband carrying electrodes for electricallystimulating the facial and mandibular nerves, to Jankelson; U.S. Pat.No. 3,590,810, entitled Biomedical body electrode, to Kopecky; U.S. Pat.No. 3,279,468, entitled Electrotherapeutic facial mask apparatus, to LeVine; U.S. Pat. No. 6,757,556, entitled Electrode sensor, to Gopinathanet al; U.S. Pat. No. 4,383,529, entitled Iontophoretic electrode device,method and gel insert, to Webster; U.S. Pat. No. 4,220,159, entitledElectrode, to Francis et al. U.S. Pat. No. 3,862,633, U.S. Pat. No.4,182,346, and U.S. Pat. No. 3,973,557, entitled Electrode, to Allisonet al; U.S. Pat. No. 4,215,696, entitled Biomedical electrode withpressurized skin contact, to Bremer et al; and U.S. Pat. No. 4,166,457,entitled Fluid self-sealing bioelectrode, to Jacobsen et al.] Thestimulator designs shown in FIGS. 4 and 5 are also self-contained units,housing the electrodes, signal electronics, and power supply. Portablestimulators are also known in the art, for example, U.S. Pat. No.7,171,266, entitled Electro-acupuncture device with stimulationelectrode assembly, to Gruzdowich. One of the novelties of the designsshown in FIGS. 4 and 5 is that the stimulator, along with acorrespondingly suitable stimulation waveform, shapes the electricfield, producing a selective physiological response by stimulating thatnerve, but avoiding substantial stimulation of nerves and tissue otherthan the target nerve, particularly avoiding the stimulation of nervesthat produce pain. The shaping of the electric field is described interms of the corresponding field equations in commonly assignedapplication US20110230938 (application Ser. No. 13/075,746) entitledDevices and methods for non-invasive electrical stimulation and theiruse for vagal nerve stimulation on the neck of a patient, to SIMON etal., which is hereby incorporated by reference.

In one embodiment, the magnetic stimulator coil 341 in FIG. 2A has abody that is similar to the electrode-based stimulator shown in FIG. 5C.To compare the electrode-based stimulator with the magnetic stimulator,refer to FIG. 5D, which shows the magnetic stimulator 530 sectionedalong its long axis to reveal its inner structure. As described below,it reduces the volume of conducting material that must surround atoroidal coil, by using two toroids, side-by-side, and passingelectrical current through the two toroidal coils in oppositedirections. In this configuration, the induced electrical current willflow from the lumen of one toroid, through the tissue and back throughthe lumen of the other, completing the circuit within the toroids'conducting medium. Thus, minimal space for the conducting medium isrequired around the outside of the toroids at positions near from thegap between the pair of coils. An additional advantage of using twotoroids in this configuration is that this design will greatly increasethe magnitude of the electric field gradient between them, which iscrucial for exciting long, straight axons such as the vagus nerve andcertain peripheral nerves.

As seen in FIG. 5D, a mesh 531 has openings that permit a conducting gel(within 351 in FIG. 2A) to pass from the inside of the stimulator to thesurface of the patient's skin at the location of nerve or tissuestimulation. Thus, the mesh with openings 531 is the part of themagnetic stimulator that is applied to the skin of the patient.

FIG. 5D also shows openings at the opposite end of the magneticstimulator 530. One of the openings is an electronics port 532 throughwhich wires pass from the stimulator coil(s) to the impulse generator(310 in FIG. 2A). The second opening is a conducting gel port 533through which conducting gel (351 in FIG. 2A) may be introduced into themagnetic stimulator 530 and through which a screw-driven piston arm maybe introduced to dispense conducting gel through the mesh 531. The gelitself is contained within cylindrical-shaped but interconnectedconducting medium chambers 534 that are shown in FIG. 5D. The depth ofthe conducting medium chambers 534, which is approximately the height ofthe long axis of the stimulator, affects the magnitude of the electricfields and currents that are induced by the magnetic stimulator device[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (4, 2001): 434-441].

FIG. 5D also show the coils of wire 535 that are wound around toroidalcores 536, consisting of high-permeability material (e.g., Supermendur).Lead wires (not shown) for the coils 535 pass from the stimulatorcoil(s) to the impulse generator (310 in FIG. 2A) via the electronicsport 532. Different circuit configurations are contemplated. If separatelead wires for each of the coils 535 connect to the impulse generator(i.e., parallel connection), and if the pair of coils are wound with thesame handedness around the cores, then the design is for current to passin opposite directions through the two coils. On the other hand, if thecoils are wound with opposite handedness around the cores, then the leadwires for the coils may be connected in series to the impulse generator,or if they are connected to the impulse generator in parallel, then thedesign is for current to pass in the same direction through both coils.

As also seen in FIG. 5D, the coils 535 and cores 536 around which theyare wound are mounted as close as practical to the corresponding mesh531 with openings through which conducting gel passes to the surface ofthe patient's skin. As shown, each coil and the core around which it iswound is mounted in its own housing 537, the function of which is toprovide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium. A difference between thestructure of the electrode-based stimulator shown in FIG. 5C and themagnetic stimulator shown in FIG. 5D is that the conducting gel ismaintained within the chambers 57 of the electrode-based stimulator,which is generally closed on the back side of the chamber because of thepresence of the electrode 56; but in the magnetic stimulator, the holeof each toroidal core and winding is open, permitting the conducting gelto enter the interconnected chambers 534.

Application of the Stimulators to the Neck of the Patient

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3, 4 and 5 tostimulate the vagus nerve at that location in the neck, in which thestimulator device 50 or 530 in FIG. 5 is shown to be applied to thetarget location on the patient's neck as described above. For reference,FIG. 6A shows the locations of the following vertebrae: first cervicalvertebra 71, the fifth cervical vertebra 75, the sixth cervical vertebra76, and the seventh cervical vertebra 77. FIG. 6B shows the stimulator50 applied to the neck of a child, which is partially immobilized with afoam cervical collar 78 that is similar to ones used for neck injuriesand neck pain. The collar is tightened with a strap 79, and thestimulator is inserted through a hole in the collar to reach the child'sneck surface. As shown, the stimulator is turned on and off with aswitch that is located on the stimulator, and the amplitude ofstimulation may be adjusted with a control knob that is also located onthe stimulator. In other models, the stimulator may be turned on and offremotely, using a wireless controller that may be used to adjust all ofthe stimulation parameters of the controller (on/off, stimulationamplitude, frequency, etc.).

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6. As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin.

The vagus nerve 60 is identified in FIG. 7, along with the carotidsheath 61 that is identified there in bold peripheral outline. Thecarotid sheath encloses not only the vagus nerve, but also the internaljugular vein 62 and the common carotid artery 63. Features that may beidentified near the surface of the neck include the external jugularvein 64 and the sternocleidomastoid muscle 65. Additional organs in thevicinity of the vagus nerve include the trachea 66, thyroid gland 67,esophagus 68, scalenus anterior muscle 69, and scalenus medius muscle70. The sixth cervical vertebra 76 is also shown in FIG. 7, with bonystructure indicated by hatching marks.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical stimulation devicesthat are disclosed herein. Stimulation may be performed on the left orright vagus nerve or on both of them simulataneously or alternately. Theposition and angular orientation of the device are adjusted about thatlocation until the patient perceives stimulation when current is passedthrough the stimulator electrodes. The applied current is increasedgradually, first to a level wherein the patient feels sensation from thestimulation. The power is then increased, but is set to a level that isless than one at which the patient first indicates any discomfort.Straps, harnesses, or frames are used to maintain the stimulator inposition. The stimulator signal may have a frequency and otherparameters that are selected to produce a therapeutic result in thepatient. Stimulation parameters for each patient are adjusted on anindividualized basis. Ordinarily, the amplitude of the stimulationsignal is set to the maximum that is comfortable for the patient, andthen the other stimulation parameters are adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2. The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period tau may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation. More generally, there may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of about 1 to about 1000 microseconds (i.e., about 1 to about10 KHz), preferably about 200 microseconds (about 5 KHz). A burstfollowed by a silent inter-burst interval repeats at 1 to 5000 burstsper second (bps), preferably at 5-50 bps, and even more preferably 10-25bps stimulation (10-25 Hz). The preferred shape of each pulse is a fullsinusoidal wave, although triangular or other shapes may be used aswell.

An exemplary noninvasive vagus nerve stimulation treatment is conductedfor two minutes. For prophylactic treatments, such as a treatment toavert a stroke or transient ischemic attack, the therapy may consist of:(1) 3 treatments/day; (2) two treatments, either consecutively, orseparated by 5 min, 3×/day; (3) 3 treatments, either consecutively orseparated by 5 min, 2×/day; or (4) 2 or 3 treatments, eitherconsecutively or separated by 5 minutes, up to 10×/day. Initiation of atreatment may begin when an imminent stroke or TIA is forecasted (seebelow), or in a risk-factor reduction program it may be performedthroughout the day beginning after the patient arises in the morning.

For an acute treatment, such as treatment of acute stroke, the therapymay consist of: (1) 1 treatment at onset of symptoms; (2) 1 treatment atonset of symptoms, followed by another treatment at 15 min; or (3) 1treatment every hour.

For long term treatment of an acute insult such as occurs during therehabilitation of a stroke patient, the therapy may consist of: (1) 3treatments/day; (2) 2 treatments, either consecutively or separated by 5min, 3×/day; (3) 3 treatments, either consecutively or separated by 5min, 2×/day; (4) 2 or 3 treatments, either consecutively or separated by5 min, up to 10×/day; or (5) 1, 2 or 3 treatments, either consecutivelyor separated by 5 min, every 15, 30, 60 or 120 min.

For all of the treatments listed above, one may alternate treatmentbetween left and right sides, or in the case of stroke or migraine thatexhibits hemispheric preferences, one may treat ipsilateral orcontralateral to the stroke-hemisphere or headache side, respectively.Or for a single treatment, one may treat one minute on one side followedby one minute on the opposite side. For patients experiencingintermittent symptoms, the treatment may be performed only when thepatient is symptomatic. Different stimulation parameters may also beselected as the course of the patient's disease changes. Variations ofthese treatment paradigms may be chosen on a patient-by-patient basis.However, it is understood that parameters of the stimulation protocolmay be varied in response to heterogeneity in the symptoms of patients.Different stimulation parameters may also be selected as the course ofthe patient's condition changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

The general stimulation schedules described above, or an individualizedprotocol fashioned for each patient, are designed or justified usingconcepts that are analogous to the selection of drug treatmentprotocols. For drugs, pharmacological dose-response experiments measurethe cumulative effect of a bolus of the drug on the physiologicalparameter that is to be controlled as a function of time (e.g., bloodpressure). After administration of the drug, the effective concentrationof the drug decreases, typically with an exponentially decayinghalf-life, but sometimes with a complex decay pattern, and the effect ofthe drug on the physiological parameter also eventually decreases. Thesituation is similar with vagus nerve stimulation. The effectiveness ofvagus nerve stimulation on a physiological parameter may also beconsidered quantitatively (e.g., EEG-derived index of cerebral ischemia,see: FERREE T C, Hwa RC. Electrophysiological measures of acute cerebralischaemia. Phys Med Biol 50(17, 2005):3927-3939). The effectiveness is afunction of the stimulation voltage, the duration of the stimulation,and if stimulation has ceased, the time since cessation of the laststimulation. Accordingly, the numerical value of an “Accumulated VagusNerve Stimulation” with a particular waveform may be denoted as S(t) andmay for present purposes be represented as one that increases at a rateproportional to the stimulation voltage V and decays with a timeconstant TAU_(P), such that after prolonged stimulation, the accumulatedstimulation effectiveness will saturate at a value equal to the productof V and TAU_(P). Thus, if T_(P) is the duration of a stimulus pulse,then for time t<T_(P), S(t)=V_(P)[1−exp(−t/TAU_(P))]+S₀ exp(−t/TAU_(P)).For t>T_(P), S(t)=S(T_(P)) exp(−[t−T_(P)]/TAU_(P)), where the time t ismeasured from the start of a pulse, S₀ is the value of S when t=0, andthe stimulation voltage V may be expressed in units of the volts neededto first elicit a response on the part of the patient. Because eachpatient may have a different value of TAU_(P), the stimulus protocolneeded to maintain the physiological value above or below a certainpre-determined value may likewise vary from patient to patient. If thedecay of the nerve stimulation effect is complex, a model morecomplicated than simple exponential decay should be used, analogous tomore complex models used in pharmacokinetics and pharmacodymanics.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a additional sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect.

For example, the hypothalamus is well known to be responsive to thepresence of bright light, so exposing the patient to bright light thatis fluctuating with the same stimulation frequency as the vagus nerve(or a multiple of that frequency) may be performed in an attempt toenhance the role of the hypothalamus in producing the desiredtherapeutic effect. Such paired stimulation does not necessarily relyupon neuronal plasticity and is in that sense different from otherreports of paired stimulation [Navzer D. ENGINEER, Jonathan R. Riley,Jonathan D. Seale, Will A. Vrana, Jai A. Shetake, Sindhu P. Sudanagunta,Michael S. Borland and Michael P. Kilgard. Reversing pathological neuralactivity using targeted plasticity. Nature 470(7332, 2011):101-104;PORTER BA, Khodaparast N, Fayyaz T, Cheung R J, Ahmed SS, Vrana W A,Rennaker R L 2nd, Kilgard MP. Repeatedly pairing vagus nerve stimulationwith a movement reorganizes primary motor cortex. Cereb Cortex 22(10,2012):2365-2374].

Selection of stimulation parameters to preferentially stimulateparticular regions of the brain may be done empirically, wherein a setof stimulation parameters are chosen, and the responsive region of thebrain is measured using fMRI or a related imaging method [CHAE J H,Nahas Z, Lomarev M, Denslow S, Lorberbaum J P, Bohning D E, George M S.A review of functional neuroimaging studies of vagus nerve stimulation(VNS). J Psychiatr Res. 37(6, 2003):443-455; CONWAY C R, Sheline Y I,Chibnall J T, George M S, Fletcher J W, Mintun M A. Cerebral blood flowchanges during vagus nerve stimulation for depression. Psychiatry Res.146(2, 2006):179-84]. Thus, by performing the imaging with differentsets of stimulation parameters, a database may be constructed, such thatthe inverse problem of selecting parameters to match a particular brainregion may be solved by consulting the database.

Stimulation waveforms may also be constructed by superimposing or mixingthe burst waveform shown in FIG. 2, in which each component of themixture may have a different period T, effectively mixing differentburst-per-second waveforms. The relative amplitude of each component ofthe mixture may be chosen to have a weight according to correlations indifferent bands in an EEG for a particular resting state network. Thus,MANTINI et al performed simultaneous fMRI and EEG measurements and foundthat each resting state network has a particular EEG signature [see FIG.3 in: MANTINI D, Perrucci M G, Del Gratta C, Romani G L, Corbetta M.Electrophysiological signatures of resting state networks in the humanbrain. Proc Natl Acad Sci USA 104(32, 2007):13170-13175]. They reportedrelative correlations in each of the following bands, for each restingstate network that was measured: delta (1-4 Hz), theta (4-8 Hz), alpha(8-13 Hz), beta (13-30 Hz), and gamma (30-50 Hz) rhythms. Forrecently-identified resting state networks, measurement of thecorresponding signature EEG networks will have to be performed.

According to the present embodiment of the invention, multiple signalsshown in FIG. 2 are constructed, with periods T that correspond to alocation near the midpoint of each of the EEG bands (e.g., using theMINATI data, T equals approximately 0.4 sec, 0.1667 sec, 0.095 sec,0.0465 sec, and 0.025 sec, respectively). A more comprehensive mixturecould also be made by mixing more than one signal for each band. Thesesignals are then mixed, with relative amplitudes corresponding to theweights measured for any particular resting state network, and themixture is used to stimulate the vagus nerve of the patient. Phasesbetween the mixed signals are adjusted to optimize the fMRI signal forthe resting state network that is being stimulated, thereby producingentrainment with the resting state network. Stimulation of a network mayactivate or deactivate a network, depending on the detailedconfiguration of adrenergic receptors within the network and their rolesin enhancing or depressing neural activity within the network, as wellas subsequent network-to-network interactions. It is understood thatvariations of this method may be used when different combined fMRI-EEGprocedures are employed and where the same resting state may havedifferent EEG signatures, depending on the circumstances [WU C W, Gu H,Lu H, Stein E A, Chen J H, Yang Y. Frequency specificity of functionalconnectivity in brain networks. Neuroimage 42(3, 2008):1047-1055; LAUFSH. Endogenous brain oscillations and related networks detected bysurface EEG-combined fMRI. Hum Brain Mapp 29(7, 2008):762-769; MUSSO F,Brinkmeyer J, Mobascher A, Warbrick T, Winterer G. Spontaneous brainactivity and EEG microstates. A novel EEG/fMRI analysis approach toexplore resting-state networks. Neuroimage 52(4, 2010):1149-1161;ESPOSITO F, Aragri A, Piccoli T, Tedeschi G, Goebel R, Di Salle F.Distributed analysis of simultaneous EEG-fMRI time-series: modeling andinterpretation issues. Magn Reson Imaging 27(8, 2009):1120-1130; FREYERF, Becker R, Anami K, Curio G, Villringer A, Ritter P.Ultrahigh-frequency EEG during fMRI: pushing the limits ofimaging-artifact correction. Neuroimage 48(1, 2009):94-108]. Once thenetwork is entrained, one may also attempt to change the signature EEGpattern of a network, by slowly changing the frequency content of thestimulation & EEG pattern of the network to which the stimulator isinitially entrained. An objective in this case would be to modify thefrequency content of the resting state signature EEG.

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of skin pain or muscle twitches.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted. Alternatively, the selection ofparameter values may involve tuning as understood in control theory, andas described below. It is understood that parameters may also be variedrandomly in order to simulate normal physiological variability, therebypossibly inducing a beneficial response in the patient [Buchman T G.Nonlinear dynamics, complex systems, and the pathobiology of criticalillness. Curr Opin Crit Care 10(5, 2004):378-82].

Use of Control Theory Methods to Improve Treatment of IndividualPatients

The vagus nerve stimulation may employ methods of control theory (e.g.,feedback) in an attempt to compensate for motion of the stimulatorrelative to the vagus nerve; to avoid potentially dangerous situationssuch as excessive heart rate; and to maintain measured EEG bands (e.g.,delta, theta, alpha, beta) within predetermined ranges, in attempt topreferentially activate particular resting state networks. Thus, withthese methods, the parameters of the vagus nerve stimulation may bechanged automatically, depending on physiological measurements that aremade, in attempt to maintain the values of the physiological signalswithin predetermined ranges.

Measurement of the patient's EEG is preferably performed as part of onedisclosed method for selecting the parameters of vagus nervestimulation, as described in the previous section. The EEG also providesdynamic physiological data concerning the onset and course of an acutestroke [JORDAN KG. Emergency EEG and continuous EEG monitoring in acuteischemic stroke. J Clin Neurophysiol 21(5, 2004):341-352; FERREE T C,Hwa R C. Electrophysiological measures of acute cerebral ischaemia. PhysMed Biol 50(17, 2005):3927-3939].

It is understood that the effects of vagus nerve stimulation on surfaceEEG waveforms may be difficult to detect [Michael BEWERNITZ, GeorgesGhacibeh, Onur Seref, Panos M. Pardalos, Chang-Chia Liu, and BasimUthman. Quantification of the impact of vagus nerve stimulationparameters on electroencephalographic measures. AIP Conf. Proc. DATAMINING, SYSTEMS ANALYSIS AND OPTIMIZATION IN BIOMEDICINE; Nov. 5, 2007,Volume 953, pp. 206-219], but they may exist nevertheless [KOO B. EEGchanges with vagus nerve stimulation. J Clin Neurophysiol. 18(5,2001):434-41; KUBA R, Guzaninová M, Brázdil M, Novák Z, Chrastina J,Rektor I. Effect of vagal nerve stimulation on interictal epileptiformdischarges: a scalp EEG study. Epilepsia. 43(10, 2002):1181-8; RIZZO P,Beelke M, De Carli F, Canovaro P, Nobili L, Robert A, Formaro P,Tanganelli P, Regesta G, Ferrillo F. Modifications of sleep EEG inducedby chronic vagus nerve stimulation in patients affected by refractoryepilepsy. Clin Neurophysiol. 115(3, 2004):658-64].

When stimulating the vagus nerve, motion variability may often beattributable to the patient's breathing, which involves contraction andassociated change in geometry of the sternocleidomastoid muscle that issituated close to the vagus nerve (identified as 65 in FIG. 7).Modulation of the stimulator amplitude to compensate for thisvariability may be accomplished by measuring the patient's respiratoryphase, or more directly by measuring movement of the stimulator, thenusing controllers (e.g., PID controllers) that are known in the art ofcontrol theory, as now described.

FIG. 8 is a control theory representation of the disclosed vagus nervestimulation methods. As shown there, the patient, or the relevantphysiological component of the patient, is considered to be the “System”that is to be controlled. The “System” (patient) receives input from the“Environment.” For example, the environment would include ambienttemperature, light, and sound. If the “System” is defined to be only aparticular physiological component of the patient, the “Environment” mayalso be considered to include physiological systems of the patient thatare not included in the “System”. Thus, if some physiological componentcan influence the behavior of another physiological component of thepatient, but not vice versa, the former component could be part of theenvironment and the latter could be part of the system. On the otherhand, if it is intended to control the former component to influence thelatter component, then both components should be considered part of the“System.”

The System also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may include thecontrol unit 330 in FIG. 2. Feedback in the schema shown in FIG. 8 ispossible because physiological measurements of the System are made usingsensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller.

The preferred sensors will include ones ordinarily used for ambulatorymonitoring. For example, the sensors may comprise those used inconventional Holter and bedside monitoring applications, for monitoringheart rate and variability, ECG, respiration depth and rate, coretemperature, hydration, blood pressure, brain function, oxygenation,skin impedance, and skin temperature. The sensors may be embedded ingarments or placed in sports wristwatches, as currently used in programsthat monitor the physiological status of soldiers [G. A. SHAW, A.M.Siegel, G. Zogbi, and T. P. Opar. Warfighter physiological andenvironmental monitoring: a study for the U.S. Army Research Institutein Environmental Medicine and the Soldier Systems Center. MIT LincolnLaboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141]. The ECG sensorsshould be adapted to the automatic extraction and analysis of particularfeatures of the ECG, for example, indices of P-wave morphology, as wellas heart rate variability indices of parasympathetic and sympathetictone. Measurement of respiration using noninvasive inductiveplethysmography, mercury in silastic strain gauges or impedancepneumography is particularly advised, in order to account for theeffects of respiration on the heart. A noninvasive accelerometer mayalso be included among the ambulatory sensors, in order to identifymotion artifacts. An event marker may also be included in order for thepatient to mark relevant circumstances and sensations.

For brain monitoring, the sensors may comprise ambulatory EEG sensors[CASSON A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst 34(2010):195-212]. In the present application, the features would includeEEG bands (e.g., delta, theta, alpha, beta).

Detection of the phase of respiration may be performed non-invasively byadhering a thermistor or thermocouple probe to the patient's cheek so asto position the probe at the nasal orifice. Strain gauge signals frombelts strapped around the chest, as well as inductive plethysmographyand impedance pneumography, are also used traditionally tonon-invasively generate a signal that rises and falls as a function ofthe phase of respiration. Respiratory phase may also be inferred frommovement of the sternocleidomastoid muscle that also causes movement ofthe vagus nerve stimulator during breathing, measured usingaccelerometers attached to the vagus nerve stimulator, as describedbelow. After digitizing such signals, the phase of respiration may bedetermined using software such as “puka”, which is part ofPhysioToolkit, a large published library of open source software anduser manuals that are used to process and display a wide range ofphysiological signals [GOLDBERGER A L, Amaral LAN, Glass L, Hausdorff JM, Ivanov PCh, Mark R G, Mietus J E, Moody G B, Peng C K, Stanley H E.PhysioBank, PhysioToolkit, and PhysioNet: Components of a New ResearchResource for Complex Physiologic Signals. Circulation 101(23,2000):e215-e220] available from PhysioNet, M.I.T. Room E25-505A, 77Massachusetts Avenue, Cambridge, Mass. 02139]. In one embodiment of thepresent invention, the control unit 330 contains an analog-to-digitalconverter to receive such analog respiratory signals, and software forthe analysis of the digitized respiratory waveform resides within thecontrol unit 330. That software extracts turning points within therespiratory waveform, such as end-expiration and end-inspiration, andforecasts future turning-points, based upon the frequency with whichwaveforms from previous breaths match a partial waveform for the currentbreath. The control unit 330 then controls the impulse generator 310,for example, to stimulate the selected nerve only during a selectedphase of respiration, such as all of inspiration or only the firstsecond of inspiration, or only the expected middle half of inspiration.

It may be therapeutically advantageous to program the control unit 330to control the impulse generator 310 in such a way as to temporallymodulate stimulation by the magnetic stimulator coils or electrodes,depending on the phase of the patient's respiration. In patentapplication JP2008/081479A, entitled Vagus nerve stimulation system, toYOSHIHOTO, a system is also described for keeping the heart rate withinsafe limits. When the heart rate is too high, that system stimulates apatient's vagus nerve, and when the heart rate is too low, that systemtries to achieve stabilization of the heart rate by stimulating theheart itself, rather than use different parameters to stimulate thevagus nerve. In that disclosure, vagal stimulation uses an electrode,which is described as either a surface electrode applied to the bodysurface or an electrode introduced to the vicinity of the vagus nervevia a hypodermic needle. That disclosure is unrelated to stroke ortransient ischemic attack problems that are addressed here, but it doesconsider stimulation during particular phases of the respiratory cycle,for the following reason. Because the vagus nerve is near the phrenicnerve, Yoshihoto indicates that the phrenic nerve will sometimes beelectrically stimulated along with the vagus nerve. The presentapplicants have not experienced this problem, so the problem may be oneof a misplaced electrode. In any case, the phrenic nerve controlsmuscular movement of the diaphragm, so consequently, stimulation of thephrenic nerve causes the patient to hiccup or experience irregularmovement of the diaphragm, or otherwise experience discomfort. Tominimize the effects of irregular diaphragm movement, Yoshihoto's systemis designed to stimulate the phrenic nerve (and possibly co-stimulatethe vagus nerve) only during the inspiration phase of the respiratorycycle and not during expiration. Furthermore, the system is designed togradually increase and then decrease the magnitude of the electricalstimulation during inspiration (notably amplitude and stimulus rate) soas to make stimulation of the phrenic nerve and diaphragm gradual.

The present invention also discloses stimulation of the vagus nerve as afunction of respiratory phase, but the rationale for such stimulation isdifferent from Yoshihoto's method.

In some embodiments of the invention, overheating of the magneticstimulator coil may also be minimized by optionally restricting themagnetic stimulation to particular phases of the respiratory cycle,allowing the coil to cool during the other phases of the respiratorycycle. Alternatively, greater peak power may be achieved per respiratorycycle by concentrating all the energy of the magnetic pulses intoselected phases of the respiratory cycle.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the magnetic stimulator coil or electrodes, so as toachieve and maintain the heart rate within safe or desired limits. Inthat case, the parameters of the stimulation are individually raised orlowered in increments (power, frequency, etc.), and the effect as anincreased, unchanged, or decreased heart rate is stored in the memory ofthe control unit 330. When the heart rate changes to a value outside thespecified range, the control unit 330 automatically resets theparameters to values that had been recorded to produce a heart ratewithin that range, or if no heart rate within that range has yet beenachieved, it increases or decreases parameter values in the directionthat previously acquired data indicate would change the heart rate inthe direction towards a heart rate in the desired range. Similarly, thearterial blood pressure is also recorded non-invasively in an embodimentof the invention, and as described above, the control unit 330 extractsthe systolic, diastolic, and mean arterial blood pressure from the bloodpressure waveform. The control unit 330 will then control the impulsegenerator 310 in such a way as to temporally modulate nerve stimulationby the magnetic stimulator coil or electrodes, in such a way as toachieve and maintain the blood pressure within predetermined safe ordesired limits, by the same method that was indicated above for theheart rate. Thus, even if one does not intend to treat problemsassociated with stroke, embodiments of the invention described above maybe used to achieve and maintain the heart rate and blood pressure withindesired ranges.

Let the measured output variables of the system in FIG. 8 be denoted byy_(i) (i=1 to Q); let the desired (reference or setpoint) values ofy_(i) be denoted by r_(i) and let the controller's input to the systemconsist of variables u_(j) (j=1 to P). The objective is for a controllerto select the input u_(j) in such a way that the output variables (or asubset of them) closely follows the reference signals r_(i), i.e., thecontrol error e_(i)=r_(i)−y_(i) is small, even if there is environmentalinput or noise to the system. Consider the error functione_(i)=r_(i)−y_(i) to be the sensed physiological input to the controllerin FIG. 8 (i.e., the reference signals are integral to the controller,which subtracts the measured system values from them to construct thecontrol error signal). The controller will also receive a set ofmeasured environmental signals v_(k) (k=1 to R), which also act upon thesystem as shown in FIG. 8.

The functional form of the system's input u(t) is constrained to be asshown in FIGS. 2D and 2E. Ordinarily, a parameter that needs adjustingis the one associated with the amplitude of the signal shown in FIG. 2.As a first example of the use of feedback to control the system,consider the problem of adjusting the input u(t) from the vagus nervestimulator (i.e., output from the controller) in order to compensate formotion artifacts.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error (e=r−y) in the intended (r) versus actual (y) nervestimulation amplitude that needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr #300Coppell, Tex. 75019. One or more accelerometer is attached to thepatient's neck, and one or more accelerometer is attached to the head ofthe stimulator in the vicinity of where the stimulator contacts thepatient. Because the temporally integrated outputs of the accelerometersprovide a measurement of the current position of each accelerometer, thecombined accelerometer outputs make it possible to measure any movementof the stimulator relative to the underlying tissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed [KNAPPERTZ V A,Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1, 1998):82-5]. The ultrasound probe is configured to have the sameshape as the stimulator, including the attachment of one or moreaccelerometer. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed or helped to perform neckmovements, breathe deeply so as to contract the sternocleidomastoidmuscle, and generally simulate possible motion that may accompanyprolonged stimulation with the stimulator. This would include possibleslippage or movement of the stimulator relative to an initial positionon the patient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmurto,Przemystaw Ptonecki, Jacek Starzynski, Stanislaw Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator (u) in proportion to the inferred deviationof the amplitude of the electric field in the vicinity of the vagusnerve, relative to its desired value.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the form dy_(i)/dt=F_(i)(t,{y_(i)},{u_(j)},{v_(k)};{r_(i)}), where t is time andwhere in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F_(i) is as a linear combination of the state andinput variables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Thus, for example, asingle-input single-output system (dropping the subscripts on variables)may have input from a controller of the form:

${u(t)} = {{K_{p}{e(t)}} + {K_{i}{\int_{0}^{t}{{e(\tau)}{\tau}}}} + {K_{d}\frac{e}{t}}}$

where the parameters for the controller are the proportional gain(K_(p)), the integral gain (K_(i)) and the derivative gain (K_(d)). Thistype of controller, which forms a controlling input signal with feedbackusing the error e=r−y, is known as a PID controller(proportional-integral-derivative).

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [LI, Y., Ang, K. H. and Chong, G. C. Y. Patents, software andhardware for PID control: an overview and analysis of the current art.IEEE Control Systems Magazine, 26 (1, 2006): 42-54; Karl Johan Åström &Richard M. Murray. Feedback Systems: An Introduction for Scientists andEngineers. Princeton N.J.: Princeton University Press, 2008; FinnHAUGEN. Tuning of PID controllers (Chapter 10) In: Basic Dynamics andControl. 2009. ISBN 978-82-91748-13-9. TechTeach, Enggravhøgda 45,N-3711 Skien, Norway. http://techteach.no., pp. 129-155; Dingyu XUE,YangQuan Chen, Derek P. Atherton. PID controller design (Chapter 6), In:Linear Feedback Control Analysis and Design with MATLAB. Society forIndustrial and Applied Mathematics (SIAM).3600 Market Street, 6th Floor,Philadelphia, Pa. (2007), pp. 183-235; Jan JANTZEN, Tuning Of Fuzzy PIDControllers, Technical University of Denmark, report 98-H 871, Sep. 30,1998].

Commercial versions of PID controllers are available, and they are usedin 90% of all control applications. To use such a controller, forexample, in an attempt to maintain the EEG gamma band at a particularlevel relative to the alpha band, one could set the integral andderivative gains to zero, increase the proportional gain (amplitude ofthe stimulation) until the relative gamma band level starts tooscillate, and then measure the period of oscillation. The PID wouldthen be set to its tuned parameter values.

Although classical control theory works well for linear systems havingone or only a few system variables, special methods have been developedfor systems in which the system is nonlinear (i.e., the state-spacerepresentation contains nonlinear differential equations), or multipleinput/output variables. Such methods are important for the presentinvention because the physiological system to be controlled will begenerally nonlinear, and there will generally be multiple outputphysiological signals. It is understood that those methods may also beimplemented in the controller shown in FIG. 8 [Torkel GLAD and LennartLjung. Control Theory. Multivariable and Nonlinear Methods. New York:Taylor and Francis, 2000; Zdzislaw BUBNICKI. Modern Control Theory.Berlin: Springer, 2005].

The controller shown in FIG. 8 may also make use of feed-forward methods[Coleman BROSILOW, Babu Joseph. Feedforward Control (Chapter 9) In:Techniques of Model-Based Control. Upper Saddle River, N.J.: PrenticeHall PTR, 2002. pp, 221-240]. Thus, the controller in FIG. 8 may be atype of predictive controller, methods for which have been developed inother contexts as well, such as when a model of the system is used tocalculate future outputs of the system, with the objective of choosingamong possible inputs so as to optimize a criterion that is based onfuture values of the system's output variables.

Performance of system control can be improved by combining the feedbackclosed-loop control of a PID controller with feed-forward control,wherein knowledge about the system's future behavior can be fed forwardand combined with the PID output to improve the overall systemperformance. For example, if the sensed environmental input in FIG. 8 issuch the environmental input to the system will have a deleteriouseffect on the system after a delay, the controller may use thisinformation to provide anticipatory control input to the system, so asto avert or mitigate the deleterious effects that would have been sensedonly after-the-fact with a feedback-only controller.

A mathematical model of the system is needed in order to perform thepredictions of system behavior, e.g., make predictions concerning thepatient's future status regarding a stroke or transient ischemic attack.Models that are completely based upon physical first principles(white-box) are rare, especially in the case of physiological systems.Instead, most models that make use of prior structural and mechanisticunderstanding of the system are so-called grey-box models. If themechanisms of the systems are not sufficiently understood in order toconstruct a white or grey box model, a black-box model may be usedinstead. Such black box models comprise autoregressive models [TimBOLLERSLEV. Generalized autoregressive condiditional heteroskedasticity.Journal of Econometrics 31 (1986):307-327], or those that make use ofprincipal components [James H. STOCK, Mark W. Watson. Forecasting withMany Predictors, In: Handbook of Economic Forecasting. Volume 1,G.Elliott, C. W. J. Granger and A. Timmermann, eds (2006) Amsterdam:Elsevier B. V, pp 515-554], Kalman filters [Eric A. WAN and Rudolph vander Merwe. The unscented Kalman filter for nonlinear estimation, In:Proceedings of Symposium 2000 on Adaptive Systems for Signal Processing,Communication and Control (AS-SPCC), IEEE, Lake Louise, Alberta, Canada,October, 2000, pp 153-158], wavelet transforms [O. RENAUD, J.-L. Stark,F. Murtagh. Wavelet-based forecasting of short and long memory timeseries. Signal Processing 48 (1996):51-65], hidden Markov models [SamROWEIS and Zoubin Ghahramani. A Unifying Review of Linear GaussianModels. Neural Computation 11(2, 1999): 305-345], or artificial neuralnetworks [Guoquiang ZHANG, B. Eddy Patuwo, Michael Y. Hu. Forecastingwith artificial neural networks: the state of the art. InternationalJournal of Forecasting 14 (1998): 35-62].

For the present invention, if a black-box model must be used, thepreferred model will be one that makes use of support vector machines. Asupport vector machine (SVM) is an algorithmic approach to the problemof classification within the larger context of supervised learning. Anumber of classification problems whose solutions in the past have beensolved by multi-layer back-propagation neural networks, or morecomplicated methods, have been found to be more easily solvable by SVMs[Christopher J.C. BURGES. A tutorial on support vector machines forpattern recognition. Data Mining and Knowledge Discovery 2 (1998),121-167; J. A. K. SUYKENS, J. Vandewalle, B. De Moor. Optimal Control byLeast Squares Support Vector Machines. Neural Networks 14 (2001):23-35;SAPANKEVYCH, N. and Sankar, R. Time Series Prediction Using SupportVector Machines: A Survey. IEEE Computational Intelligence Magazine 4(2,2009): 24-38; PRESS, W H; Teukolsky, SA; Vetterling, WT; Flannery, B P(2007). Section 16.5. Support Vector Machines. In: Numerical Recipes TheArt of Scientific Computing (3rd ed.). New York: Cambridge UniversityPress].

Consider now the problem of predicting and possibly averting a stroke ortransient ischemic attack. The example assumes that vagus nervestimulation can be applied as described above, but the stimulation isapplied only when the invention's feedforward system predicts that astroke or transient ischemic attack is imminent. Candidates for thedisclosed forecasting methods include individuals who have had a recenttransient ischemic attack and are likely to suffer a stroke in the nextfew days [JOHNSTON SC, Rothwell P M, Nguyen-Huynh M N, Giles M F, ElkinsJ S, Bernstein A L, Sidney S. Validation and refinement of scores topredict very early stroke risk after transient ischaemic attack. Lancet369(9558, 2007):283-292].

A training set of physiological data will have been acquired thatincludes whether or not a stroke or transient ischemic attack is inprogress. Thus, the binary classification of the patient's state iswhether or not a stroke or transient ischemic attack is in progress, andthe data used to make the classification consist of acquiredphysiological data. The training data would preferably be acquired froma single individual, but as a practical matter the training set of datawill ordinarily be obtained from a group of individuals who volunteerfor ambulatory or hospital physiological monitoring. In general, themore physiological data that are acquired, the better the forecast willbe.

Prediction that a stroke or TIA is imminent may be based upon the likelyformation of a thrombosis or arterial embolism. In that regard, thereexists an ambulatory monitoring device that will monitor for cerebralemboli [MacKINNON AD, Aaslid R, Markus HS. Long-term ambulatorymonitoring for cerebral emboli using transcranial Doppler ultrasound.Stroke 35(1, 2004):73-8]. It measures the passage of emboli, typicallyat the middle cerebral artery, using a transcranial Doppler signal.Whereas some cerebral emboli produce symptoms of a stroke, other embolido not produce symptoms and may not be recognized by the patient.Therefore, in one embodiment of the invention, the detection of anembolus with the device mentioned above is used as input for theforecasting of a TIA or stroke, but the appearance of the embolus in andof itself does not necessarily trigger the forecast of an imminent TIAor stroke. Additional physiological variables are used to make theforecast.

Preferably, the additional physiological variables should include EEGand its derived features, heart rate (electrocardiogram leads), bloodpressure (noninvasive tonometer), respiration (e.g., abdominal andthoracic plethysmography), and motion (accelerometer). For themonitoring of drug and medications, systemic metabolism, and changes incoagulation, body chemistry may also be measure noninvasively usingtransdermal reverse iontophoresis [Leboulanger B, Guy R H,Delgado-Charro M B. Reverse iontophoresis for non-invasive transdermalmonitoring. Physiol Meas 25(3, 2004):R35-50]. Preferably, the ambulatorynoninvasive measurements would also include skin impedance(electrodermal leads), carbon dioxide (capnometry with nasual cannula),vocalization (microphones), light (light sensor), external and fingertemperature (thermometers), etc., as well as parameters of thestimulator device, all evaluated at Δ time units prior to the time atwhich binary “stroke or transient ischemic attack in progress” (yes/no)data are acquired. Many values of delta may be considered, from secondsto minutes to hours. In general, as the value of delta increases, thecalculated uncertainty of the forecast will also increase. The onset ofthe stroke or transient ischemic attack may be inferred from the data(e.g., EEG data) and/or from a patient activated event marker upon theappearance of symptoms such as sudden weakness or numbness, and dimmingor loss of vision.

The selection of ambulatory noninvasive measurements may be motivated byphysiological considerations. For example, the ECG may automaticallymonitor the presence (or forecast) of atrial fibrillation, ambulatoryblood pressure monitors for the presence of acute increases in bloodpressure, and body temperature thermometers monitors the presence ofinfection and inflammation. The status of the autonomic nervous systemis likewise monitored through heart rate variability (via the ECG) andskin impedance. The EEG may also provide evidence of the onset andprogression of ischemia [FERREE T C, Hwa R C. Electrophysiologicalmeasures of acute cerebral ischaemia. Phys Med Biol 50(17,2005):3927-3939]. However, because the detailed physiological mechanismsof ischemic events are not fully understood, and a black box model isbeing used to make the forecast, physiological variables with anuncertain relevance to ischemia may also be monitored.

For a patient who is not experiencing a stroke or transient ischemicattack, the SVM is trained to forecast the imminence of a stroke ortransient ischemic attack, Δ time units into the future, and thetraining set includes the above-mentioned physiological signals. The SVMis also trained to forecast the termination of a transient ischemicattack, Δ time units into the future, and the training set includes thetime-course of features extracted from the above-mentioned physiologicalsignals. After training the SVM, it is implemented as part of thecontroller. The controller may apply the vagus nerve stimulation as aprophylactic whenever there is a forecast of imminent stroke ortransient ischemic attack. The controller may also be programmed to turnoff the vagaus nerve stimulation when it forecasts or detects thetermination of a transient ischemic attack. It is understood that in anyevent, the patient should treat any in-progress stroke or transientischemic attack as a medical emergency and seek immediate emergencymedical attention, notwithstanding the use of vagus nerve stimulation asa prophylactic. If the stroke or transient ischemic attack is onlyforecasted, the patient should immediately seek transportation to thewaiting room of the nearest acute stroke treatment center or emergencyroom and wait at that location to see whether the predicted stroke ortransient ischemic attack happens, notwithstanding the use of vagusnerve stimulation as a prophylactic that may have prevented the event.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A method of treating or preventing a stroke and/or a transientischemic attack in a patient, comprising: positioning a device adjacentto a skin surface of the patient; generating one or more electricalimpulses with said device; and transmitting the electrical impulses toselected nerve fibers in the patient, wherein the electrical impulsesare sufficient to modify the nerve fibers, such that the stroke and/ortransient ischemic attack in the patient is treated or prevented.
 2. Themethod of claim 1 wherein the transmitting step comprises transmittingthe electrical impulses from one or more electrodes through a conductingmedium within the device.
 3. The method of claim 1 wherein theelectrical impulses are transmitted transcutaneously through an outerskin surface of the patient to generate an electrical impulse at or nearthe selected nerve fibers.
 4. The method of claim 3 further comprisinggenerating an electrical field at or near the device and shaping theelectrical field such that the electrical field is sufficient tomodulate a nerve fiber at the target region, and wherein the electricfield is not sufficient to substantially modulate a nerve or musclebetween the outer skin surface and the target region.
 5. The method ofclaim 1 wherein the device comprises a signal generator, and one or moreelectrodes coupled to the signal generator.
 6. The method of claim 4wherein the electric field at the nerve fiber at the target region isfrom about 10 V/m to about 600 V/m.
 7. The method of claim 6 wherein theelectric field is less than about 100 V/m.
 8. The method of claim 4wherein the nerve fiber at the target region is at least about 0.5 cm toabout 2 cm below an outer skin-surface of the patient.
 9. The method ofclaim 1 wherein the selected nerve fibers are associated with a vagusnerve of the patient.
 10. The method of claim 1 wherein the electricalimpulses comprise bursts of pulses with a frequency of about 1 to about100 bursts per second.
 11. The method of claim 10 wherein each burstcontains about 1 to about 20 pulses.
 12. The method of claim 10 whereinthe pulses are full sinusoidal waves.
 13. The method of claim 10 whereineach pulse is about 100 to about 1000 microseconds in duration.
 14. Themethod of claim 13 wherein the duration of a pulse within a burst isabout 200 microseconds, wherein the number of pulses per burst is from 4to 6, and wherein the number of bursts per second is from 20 to
 30. 15.The method of claim 1 wherein the selected nerve fibers control ormodulate the release of GABA, norepinephrine, or serotonin.
 16. Themethod of claim 1 wherein the electrical impulses generate an electricfield at the vagus nerve above a threshold for generating actionpotentials within A and B fibers of the vagus nerve and below athreshold for generating action potentials within C fibers of the vagusnerve.
 17. The method of claim 1 wherein the electrical impulsesgenerate an electric field at the vagus nerve above a threshold forgenerating action potentials within fibers of the vagus nerveresponsible for activating neural pathways causing release of inhibitoryneurotransmitters within a brain of the patient.
 18. The method of claim1 wherein norepinephrine is released into a resting state neural networkof the patient.
 19. The method of claim 18 wherein the resting statenetwork comprises a default mode network, an attentional network, asalience network, a part of an anterior insula and/or an anteriorcingulate cortex, or a sensory-motor network.
 20. The method of claim 1wherein the treatment is for spatial neglect or for recovery of motorskills.
 21. A device for treating or preventing a stroke or a transientischemic attack in a patient, comprising: a housing having anelectrically permeable contact surface for contacting an outer skinsurface of the patient; an energy source within the housing configuredto generate an electric field sufficient to transmit a shaped electriccurrent through the outer skin surface of the patient to a nerve at atarget region within the patient; wherein the electric current issufficient to treat or prevent the stroke or the transient ischemicattack in the patient.
 22. The device of claim 21 wherein the energysource comprises a signal generator and one or more electrodes coupledto the signal generator within the housing.
 23. The device of claim 22further comprising a conducting medium within the housing between theelectrodes and the electrically permeable contact surface.
 24. Thedevice of claim 21 wherein the energy source comprises a battery. 25.The device of claim 21 wherein the electric field comprises bursts ofpulses with a frequency of about 1 to about 100 bursts per second. 26.The device of claim 25 wherein the electric field comprises bursts ofabout 1 to about 50 pulses per burst, with each pulse being about 50 toabout 1000 microseconds in duration.
 27. The device of claim 21 whereinthe electric current is sufficient to stimulate a vagus nerve of thepatient.
 28. The device of claim 21 wherein the housing is a handhelddevice configured for contacting a surface of the skin of a patient. 29.The device of claim 21 wherein the electrical current generates anelectric field at the vagus nerve above a threshold for generatingaction potentials within A and B fibers of the vagus nerve and below athreshold for generating action potentials within C fibers of the vagusnerve.
 30. The device of claim 21 wherein the electrical currentgenerates an electric field at the vagus nerve above a threshold forgenerating action potentials within fibers of the vagus nerveresponsible for activating neural pathways causing release of inhibitoryneurotransmitters within a brain of the patient.
 31. The device of claim30 wherein the inhibitory neurotransmitters comprise GABA,norepinephrine, or serotonin.
 32. The device of claim 31 whereinnorepinephrine is released into a resting state neural network of thepatient.
 33. The device of claim 32 wherein the resting state networkcomprises a default mode network, an attentional network, a saliencenetwork, a part of an anterior insula and/or an anterior cingulatecortex, or a sensory-motor network.
 34. The device of claim 21 whereinthe treatment is for spatial neglect or for the recovery of motorskills.